Methods of synthesizing substituted pyridinone-pyridinyl compounds

ABSTRACT

The present disclosure provides methods of synthesizing a compound of Formula (P)-I. The method proceeds through several different pathways including several novel chiral separations, a Sonogashira coupling, a zinc mediated reductive cyanation, as well as through various halide containing intermediates. Also disclosed is the multi-kilogram preparation of several novel intermediates.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.63/117,053 filed Nov. 23, 2020 and U.S. Provisional Application No.63/239,596 filed Sep. 1, 2021. The disclosures of each of theseapplications are incorporated herein by reference.

SUMMARY

The present disclosure includes embodiments directed to methods ofsynthesizing a compound of Formula (P)-I, having the structure:

The methods include the chiral resolution to produce the compound ofFormula (P)-I or, in the alternative, several different intermediates inthe synthesis of Formula (P)-I. Also disclosed are alternative synthesesof several intermediates.

Definitions

Before the present compositions and methods are described, it is to beunderstood that this invention is not limited to the particularprocesses, formulations, compositions, or methodologies described, asthese may vary. It is also to be understood that the terminology used inthe description is for the purpose of describing the particular versionsor embodiments only, and is not intended to limit the scope ofembodiments herein which will be limited only by the appended claims.Unless defined otherwise, all technical and scientific terms used hereinhave the same meanings as commonly understood by one of ordinary skillin the art. Although any methods and materials similar or equivalent tothose described herein can be used in the practice or testing ofembodiments of embodiments herein, the preferred methods, devices, andmaterials are now described. All publications mentioned herein areincorporated by reference in their entirety. Nothing herein is to beconstrued as an admission that embodiments herein are not entitled toantedate such disclosure by virtue of prior invention.

It must also be noted that as used herein and in the appended claims,the singular forms “a,” “an,” and “the” include plural reference unlessthe context clearly dictates otherwise.

The transitional term “comprising,” which is synonymous with“including,” “containing,” or “characterized by,” is inclusive oropen-ended and does not exclude additional, unrecited elements or methodsteps.

In embodiments or claims where the term “comprising” is used as thetransition phrase, such embodiments can also be envisioned withreplacement of the term “comprising” with the terms “consisting of” or“consisting essentially of.”

As used herein, the term “consists of” or “consisting of” means that thecomposition, formulation or the method includes only the elements,steps, or ingredients specifically recited in the particular claimedembodiment or claim.

As used herein, the term “consisting essentially of” or “consistsessentially of” means that the composition, formulation or the methodincludes only the elements, steps or ingredients specifically recited inthe particular claimed embodiment or claim and may optionally includeadditional elements, steps or ingredients that do not materially affectthe basic and novel characteristics of the particular embodiment orclaim. For example, the only active ingredient(s) in the formulation ormethod that treats the specified condition (e.g., nutrient depletion) isthe specifically recited therapeutic(s) in the particular embodiment orclaim.

As used herein, two embodiments are “mutually exclusive” when one isdefined to be something which is different from the other. For example,an embodiment wherein two groups combine to form a cycloalkyl ismutually exclusive with an embodiment in which one group is ethyl theother group is hydrogen. Similarly, an embodiment wherein one group isCH₂ is mutually exclusive with an embodiment wherein the same group isNH.

When ranges of values are disclosed, and the notation “from n1 . . . ton2” or “between n1 . . . and n2” is used, where n1 and n2 are thenumbers, then unless otherwise specified, this notation is intended toinclude the numbers themselves and the range between them. This rangemay be integral or continuous between and including the end values. Byway of example, the range “from 2 to 6 carbons” is intended to includetwo, three, four, five, and six carbons, since carbons come in integerunits. Compare, by way of example, the range “from 1 to 3 μM(micromolar),” which is intended to include 1 μM, 3 μM, and everythingin between to any number of significant figures (e.g., 1.255 μM, 2.1 μM,2.9999 μM, etc.).

The term “about,” as used herein, is intended to qualify the numericalvalues which it modifies, denoting such a value as variable within amargin of error. When no particular margin of error, such as a standarddeviation to a mean value given in a chart or table of data, is recited,the term “about” should be understood to mean plus or minus 10% of thenumerical value of the number with which it is being used. Therefore,about 50% means in the range of 45%-55%.

In embodiments or claims the “X” in the term “MeMgX” is a halogen.

The term “chiral separation,” as used herein, refers to the separationof racemic compounds into their single or enriched atropisomers orenantiomers.

The term “substantially free” as used herein, is used interchangeablywith, the term “substantially pure”, refers to a compound which is freefrom all other compounds within the limits of detection as measured byany means including nuclear magnetic resonance (NMR), gaschromatography/mass spectroscopy (GC/MS), or liquid chromatography/massspectroscopy (LC/MS). In some embodiments, substantially free may beless than about 1.0%, less than about 0.5%, less than about 0.4%, lessthan about 0.3%, less than about 0.2%, less than about 0.1%, less thanabout 0.05%, or less than about 0.01%.

The term “interconversion” or “conformational interconversion” refers toany change between the atropisomers of this disclosure, including butnot limited to equilibration.

The term “equilibration” refers to a chemical reaction in which theforward and reverse ratio rates cancel out. Equilibration can be dynamicor static. A reaction in equilibrium need not contain equal partsreactant and product. When referring to atropisomeric compounds, theterm “equilibration” refers to when the rate of interconversion cancelsout. Atropisomers in equilibrium need not contain equal parts of eachsingle atropisomer and encompasses racemic mixtures of atropisomers,enriched mixtures of atropismers, as well as single atropisomers.

Also provided are embodiments wherein any embodiment herein may becombined with any one or more of the other embodiments, unless otherwisestated and provided the combination is not mutually exclusive.

Atropisomers are stereoisomers resulting from hindered rotation aboutsingle bonds where the steric strain barrier to rotation is high enoughto allow for the isolation of the conformers. Oki (Oki, M; Topics inStereochemistry 1983, 1) defined atropisomers as conformers thatinterconvert with a half-life of more than 1000 seconds at a giventemperature. The scope of embodiments herein as described and claimedencompasses the racemic forms of the compounds as well as the individualatropisomers (an atropisomer “substantially free” of its correspondingatropisomer) and stereoisomer-enriched mixtures, i.e. mixtures ofatropisomers.

Separation of atropisomers is possibly by chiral resolution methods suchas selective crystallization. In an atropo-enantioselective oratroposelective synthesis one atropisomer is formed at the expense ofthe other. Atroposelective synthesis may be carried out by use of chiralauxiliaries like a Corey-Bakshi-Shibata (CBS) catalyst (asymmetriccatalyst derived from proline) in the total synthesis of knipholone orby approaches based on thermodynamic equilibration when an isomerizationreaction favors one atropisomer over the other.

The term “atropisomerism” refers to a type of isomerism resulting fromhindered rotation around a single bond due to steric strain of thesubstituents. This phenomenon creates stereoisomers which display axialchirality.

The following scheme illustrates “atropisomerism” with reference tospecific pyridinone-pyridine compounds of the invention:

The bond between the B and C rings of the title compounds is hinderedand does not allow for facile rotation. The steric strain barrier torotation is sufficiently high such that individual conformers can beisolated. The compounds of the invention may also exist as atropisomers,i.e., chiral rotational isomers. The invention encompasses racemates,resolved atropisomers, and mixtures thereof. Atropisomers may beseparated by a variety of chromatographic methods, including by notlimited to supercritical fluid chromatography using a mobile phase ofcarbon dioxide and ethanol/methanol as well as simulated moving bed(SMB) chromatography with a chiral stationary phase and a mobile phase.

Atropisomers are generally stable but can often be equilibratedthermally. Atropisomers will have the same but opposite opticalrotation. Each atropisomers may have different properties when bound toan enzyme or receptor with one isomer often being more potent than theother. Atropisomers are frequently used as pharmaceutical agents. Knownexamples include Vancomycin and derivatives.

The configuration of atropisomers can be described using thenomenclature (M)- and (P)- to describe the relative position ofsubstituents as described in Bringmann, G. et. al., Angew. Chem. Int.Ed. 2005, 44, 5384 and references cited therein. Structures aredesignated as drawn but it is understood that either (P)- or (M)-isomersmay be desirable and the methods described would be useful for theinterconversion of either (P)- or (M)-stereoisomers.

DETAILED DESCRIPTION

The present disclosure includes embodiments directed to methods ofsynthesizing a compound of Formula (P)-I, having the structure:

(P)-3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-2′-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one

Scheme 1 outlines Routes A, B, C, D, and H for synthesizing a compoundof Formula (P)-I. Each of these routes feature chiral separation of anintermediate and then carrying forward a single or enriched atropisomerthrough the remainder of the synthesis of a compound of Formula (P)-I.

In some embodiments, the process for the preparation of the compound ofFormula (P)-I proceeds through Route A as follows: contacting SM-01 andSM-02 to give CPD-01, converting CPD-01 to CPD-02, contacting CPD-02 andINT-01 to give CPD-03, converting CPD-03 to CPD-04, converting CPD-04 toCPD-05, converting CPD-05 to CPD-06, subjecting CPD-06 to chiralseparation to give CPD-07, converting CPD-07 to CPD-08, convertingCPD-08 to CPD-09, converting CPD-09 to CPD-10, then contacting CPD-10and NT-02 to give Formula P-(I).

In some embodiments, the process for the preparation of the compound ofFormula (P)-I proceeds through Route B as follows: contacting SM-01 andSM-02 to give CPD-01, converting CPD-01 to CPD-02, contacting CPD-02 andINT-01 to give CPD-03, converting CPD-03 to CPD-11, subjecting CPD-11 tochiral separation to give CPD-12, converting CPD-12 to CPD-07,converting CPD-07 to CPD-08, converting CPD-08 to CPD-09, convertingCPD-09 to CPD-10, then contacting CPD-10 and INT-02 to give FormulaP-(I).

In some embodiments, the process for the preparation of the compound ofFormula (P)-I proceeds through Route C as follows: contacting SM-01 andSM-02 to give CPD-01, converting CPD-01 to CPD-02, contacting CPD-02 andINT-01 to give CPD-03, converting CPD-03 to CPD-11, subjecting CPD-11 tochiral separation to give CPD-12, converting CPD-12 to CPD-13,converting CPD-13 to CPD-08, converting CPD-08 to CPD-09, convertingCPD-09 to CPD-10, then contacting CPD-10 and INT-02 to give FormulaP-(I).

In some embodiments, the process for the preparation of the compound ofFormula (P)-I proceeds through Route D as follows: contacting SM-01 andSM-02 to give CPD-01, converting CPD-01 to CPD-02, contacting CPD-02 andINT-01 to give CPD-03, converting CPD-03 to CPD-11, subjecting CPD-11 tochiral separation to give CPD-12, converting CPD-12 to CPD-13,converting CPD-13 to CPD-14, converting CPD-14 to CPD-09, convertingCPD-09 to CPD-10, then contacting CPD-10 and INT-02 to give FormulaP-(I).

In some embodiments, the process for the preparation of the compound ofFormula (P)-I proceeds through Route H as follows: contacting SM-01 andSM-02 to give CPD-01, converting CPD-01 to CPD-02, contacting CPD-02 andINT-01 to give CPD-03, converting CPD-03 to CPD-04, converting CPD-04 toCPD-11, subjecting CPD-11 to chiral separation to give CPD-12. CMP-12 isthen carried forward to Formula P-(I) through the synthetic sequencesdescribed in Route B, Route C, or Route D.

Scheme 2 outlines Routes E, F, and G for synthesizing a compound ofFormula (P)-I. Each of these routes feature chiral separation as thelast step of the synthesis of a compound of Formula (P)-I.

In some embodiments, the process for the preparation of the compound ofFormula (P)-I proceeds through Route E as follows: contacting SM-01 andSM-02 to give CPD-01, converting CPD-01 to CPD-02, contacting CPD-02 andINT-01 to give CPD-03, converting CPD-03 to CPD-15, converting CPD-15 toCPD-16, converting CPD-16 to CPD-18, converting CPD-18 to CPD-19,contacting CPD-19 and INT-02 to give CPD-20, then subjecting CPD-20 tochiral separation to give Formula P-(I).

In some embodiments, the process for the preparation of the compound ofFormula (P)-I proceeds through Route F as follows: contacting SM-01 andSM-02 to give CPD-01, converting CPD-01 to CPD-02, contacting CPD-02 andINT-01 to give CPD-03, converting CPD-03 to CPD-17, converting CPD-17 toCPD-18, converting CPD-18 to CPD-19, contacting CPD-19 and INT-02 togive CPD-20, then subjecting CPD-20 to chiral separation to give FormulaP-(I).

In some embodiments, the process for the preparation of the compound ofFormula (P)-I proceeds through Route G as follows: contacting SM-01 andSM-02 to give CPD-01, converting CPD-01 to CPD-02, contacting CPD-02 andINT-01 to give CPD-03, converting CPD-03 to CPD-15, converting CPD-15 toCPD-17, converting CPD-17 to CPD-18, converting CPD-18 to CPD-19,contacting CPD-19 and INT-02 to give CPD-20, then subjecting CPD-20 tochiral separation to give Formula P-(I).

Scheme 3 outlines a method of synthesizing a compound of Formula (P)-I.

Scheme Alpha outlines a method of synthesizing a compound of Formula(P)-I.

Another embodiment of the present disclosure is directed to a compoundof Formula (P)-I as prepared according to Routes A, B, C, D, and H asshown in Scheme 1; Routes E, F, and G as shown in Scheme 2; the route asshown in Scheme 3, and the route as shown in Scheme Alpha.

Some embodiments of the present application describe a process for thepreparation of compound of Formula (P)-I having the structure:

-   -   comprising the steps of:

-   -   (a) contacting the compound SM-01, with the compound SM-02 in        the presence of dimethylacetemide (DMAc) to form a mixture; and

-   -   (b) contacting the mixture of (a) with an alcoholic HCl solution    -   to form the compound

and

-   -   (c) converting CPD-01 to Formula (P)-I.

In some embodiments of the forming of CPD-01, the alcoholic HCl solutionis selected from the group consisting of an isopropyl alcohol HClsolution or p-toluenesulfonic acid in dimethylacetamide (DMAc).

In some embodiments of the forming of CPD-01, the alcoholic HCl solutionis an isopropyl alcohol HCl solution.

In another embodiment of the process for the preparation of Formula(P)-I, the process further comprises contacting the compound CPD-01 withH₂SO₄ to form the compound

In another embodiment of the process for the preparation of Formula(P)-I, the process further comprises contacting the compound CPD-02 withthe compound

and a base to form the compound

In some embodiments of forming CPD-03, the base is selected from thegroup consisting of K₂CO₃, NaOH, Cs₂CO₃, and NaHCO₃.

In some embodiments, the base used to form CPD-03 is selected from thegroup consisting of K₂CO₃ and Cs₂CO₃.

In some embodiments of forming CPD-03, the base is K₂CO₃.

In some embodiments, the base used to form CPD-03 is Cs₂CO₃.

In some embodiments of the process for the preparation of Formula (P)-I,the process further comprises contacting the compound CPD-03 with CO inthe presence of a palladium catalyst, an amine base, and methanol toform the compound

In some embodiments of the forming of CPD-04, the palladium catalyst isselected from the group consisting of Pd(dppf)Cl₂,Pd(OAc)₂/Bis(diphenylphosphino)propane (DPPP), Pd(PPh₃)Cl₂,Pd(OAc)₂/Xphos, Pd(OAc)₂/Ruphos, Pd (DTBPF)Cl₂, and (BINAP)PdCl₂.

In some embodiments of the forming of CPD-04, the palladium catalyst isPd(dppf)Cl₂.

In some embodiments of the forming of CPD-04, the amine base is selectedfrom the group consisting of triethylamine, iPr₂NEt, andtetramethylethylenediamine,

In some embodiments of the forming of CPD-04, the amine base istriethylamine.

In some embodiments of the process for the preparation of Formula (P)-I,the process further comprises contacting the compound CPD-04 with achlorination reagent to form the compound

In some embodiments of the forming of CPD-05, the chlorination reagentis N-chlorosuccinimide.

In some embodiments, the forming of CPD-05 further comprises contactingCPD-04 with dichloroacetic acid.

In some embodiments of the process for the preparation of Formula (P)-I,the process further comprises hydrolyzing and desalting the compoundCPD-05 to form the compound CPD-06

In some embodiments of the process for the preparation of Formula (P)-I,the process further comprises subjecting the compound CPD-06 to chiralseparation with a chiral amine and a solvent to obtain the compound

In some embodiments of the chiral separation of the compound CPD-06, thechiral amine is selected from the group consisting of(S)-1-(naphthalen-2-yl)ethan-1-amine and(1S,2R)-2-amino-1,2-diphenylethan-1-ol.

In some embodiments of the chiral separation of the compound CPD-06, thechiral amine is (S)-1-(naphthalen-2-yl)ethan-1-amine.

In some embodiments of the chiral separation of the compound CPD-06, thechiral amine is (1S,2R)-2-amino-1,2-diphenylethan-1-ol.

In some embodiments of the chiral separation of the compound CPD-06, thesolvent is selected from the group consisting of toluene, ethylbenzene,n-butanol, anisole, DMSO, or a combination thereof.

In some embodiments of the chiral separation of the compound CPD-06, thesolvent is toluene.

In some embodiments of the chiral separation of the compound CPD-06, thesolvent is ethylbenzene.

In some embodiments of the chiral separation of the compound CPD-06, thesolvent is n-butanol.

In some embodiments of the chiral separation of the compound CPD-06, thesolvent is anisole.

In some embodiments of the chiral separation of the compound CPD-06, thesolvent is anisole and DMSO.

In some embodiments of the process for the preparation of Formula (P)-I,the process further comprises contacting the compound CPD-07 with asolvent, MeNHOMe, an amine base, and a coupling reagent to obtain thecompound

In some embodiments of contacting the compound CPD-07, the solvent isselected from DMF, dichloromethane, or a combination thereof.

In some embodiments of contacting the compound CPD-07, the solvent isDMF.

In some embodiments of contacting the compound CPD-07, the solvent isdichloromethane.

In some embodiments of the contacting the compound CPD-07, the aminebase is triethylamine.

In some embodiments of the contacting the compound CPD-07, the couplingreagent is N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride.

In some embodiments of the process for the preparation of Formula (P)-I,the process further comprises contacting the compound CPD-08 with MeMgXto obtain the compound

In some embodiments of the contacting the compound CPD-07, the MeMgX isselected from the group consisting of MeMgBr and MeMgCl.

In some embodiments of the contacting the compound CPD-07, the MeMgX isMeMgBr.

In some embodiments of the contacting the compound CPD-07, the MeMgX isMeMgCl.

In some embodiments of the process for the preparation of Formula (P)-I,the process further comprises condensing compound CPD-09 withN,N-dimethyl-formamide dimethyl acetal to obtain the compound

In some embodiments of the process for the preparation of Formula (P)-I,the process further comprises contacting the compound CPD-10 with

in the presence of a base, and forming the compound of Formula (P)-I.

In some embodiments of forming the compound of Formula (P)-I, the baseis selected from the group consisting of K₂CO₃,N,N-diisopropylethylamine (DIPEA), triethylamine (TEA), tBuOK, tBuONa,and Cs₂CO₃.

In some embodiments of forming the compound of Formula (P)-I, the baseis K₂CO₃.

Scheme 4 outlines another method of synthesizing CPD-07, CPD-08, andCPD-09 starting from CPD-03. CPD-07, CPD-08, and CPD-09 may each then becarried forward through the rest of the sequence outlined in Scheme 3 toresult in the production of the compound of Formula P-(I).

Forming CPD-04 from CPD-03 is as disclosed above.

In accordance with Scheme 4, in some embodiments, the process for thepreparation of Formula (P)-I comprises contacting the compound CPD-03with CO in the presence of a palladium catalyst, an amine base andDMF/H₂O to form the compound

In some embodiments of forming CPD-11, the palladium catalyst is(BINAP)PdCl₂.

In some embodiments of forming CPD-11, the amine base is triethylamine.

In accordance with Scheme 4, in some embodiments, the process for thepreparation of Formula (P)-I, comprises the steps of:

-   -   (a) contacting the compound CPD-03 with CO in the presence of a        palladium catalyst, an amine base, a first base, and MeOH/H₂O to        form a mixture; and    -   (b) contacting the mixture of (a) with a second base        to form the compound

In some embodiments of forming CPD-11, the palladium catalyst isPd(dppf)Cl₂·DCM.

In some embodiments of forming CPD-11, the amine base is triethylamine.

In some embodiments of forming CPD-11, the first base is Na₂CO₃.

In some embodiments of forming CPD-11, the second base is NaOH.

In some embodiments of the process for the preparation of Formula (P)-I,the process further comprises contacting the compound CPD-04 with a baseto form the compound

In some embodiments of forming CPD-11, the base is selected from LiOH orNaOH.

In some embodiments of forming CPD-11, the base is LiOH.

In some embodiments of forming CPD-11, the base is NaOH.

In some embodiments of the process for the preparation of Formula (P)-I,the process further comprises subjecting the compound CPD-11 to chiralseparation with a chiral amine and a solvent to obtain the compound

In some embodiments of the chiral separation of the compound CPD-11, thechiral amine is selected from the group consisting of(S)-1-(naphthalen-2-yl)ethan-1-amine and(1S,2R)-2-amino-1,2-diphenylethan-1-ol.

In some embodiments of the chiral separation of the compound CPD-11, thechiral amine is (S)-1-(naphthalen-2-yl)ethan-1-amine.

In some embodiments of the chiral separation of the compound CPD-11, thechiral amine is (1S,2R)-2-amino-1,2-diphenylethan-1-ol.

In some embodiments of the chiral separation of the compound CPD-11, thesolvent is selected from the group consisting of toluene, ethylbenzene,n-butanol, anisole, DMSO, or a combination thereof.

In some embodiments of the chiral separation of the compound CPD-11, thesolvent is toluene.

In some embodiments of the chiral separation of the compound CPD-11, thesolvent is ethylbenzene.

In some embodiments of the chiral separation of the compound CPD-11, thesolvent is n-butanol.

In some embodiments of the chiral separation of the compound CPD-11, thesolvent is anisole.

In some embodiments of the chiral separation of the compound CPD-11, thesolvent is anisole and DMSO.

In some embodiments of the process for the preparation of Formula (P)-I,the process further comprises contacting the compound CPD-12 with achlorination reagent to form the compound

In some embodiments of forming CPD-07, the chlorination reagent isN-chlorosuccinimide.

In some embodiments, the forming of CPD-07 further comprises contactingCPD-12 with dichloroacetic acid.

In another embodiment of the process for the preparation of Formula(P)-I, the process further comprises contacting the compound CPD-12 witha solvent, MeNHOMe, an amine base, and a coupling reagent to obtain thecompound

In some embodiments of contacting the compound CPD-12, the solvent isselected from DMF, dichloromethane, or a combination thereof.

In some embodiments of contacting the compound CPD-12, the solvent isDMF.

In some embodiments of contacting the compound CPD-12, the solvent isdichloromethane.

In some embodiments of contacting the compound CPD-12, the amine base istriethylamine.

In some embodiments of contacting the compound CPD-12, the couplingreagent is N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride.

In some embodiments of the process for the preparation of Formula (P)-I,the process further comprises contacting the compound CPD-13 with achlorination reagent to form the compound

In some embodiments of the forming of CPD-08, the chlorination reagentis N-chlorosuccinimide.

In some embodiments, the forming of CPD-08 further comprises contactingCPD-13 with dichloroacetic acid.

In another embodiment of the process for the preparation of Formula(P)-I, the process further comprises contacting the compound CPD-13 withMeMgX to obtain the compound

In some embodiments of the contacting the compound CPD-13, the MeMgX isselected from the group consisting of MeMgBr and MeMgCl.

In some embodiments of the contacting the compound CPD-13, the MeMgX isMeMgBr.

In some embodiments of the contacting the compound CPD-13, the MeMgX isMeMgCl.

In some embodiments of the process for the preparation of Formula (P)-I,the process further comprises contacting the compound CPD-14 with achlorination reagent to form the compound

In some embodiments of the forming of CPD-09, the chlorination reagentis N-chlorosuccinimide.

In some embodiments, the forming of CPD-09 further comprises contactingCPD-14 with dichloroacetic acid.

Scheme 5 outlines another method of synthesizing a Formula (P)-I viaeither CPD-15 or CPD-17 starting from CPD-03. Chiral separation isutilized to produce Formula (P)-I.

In accordance with the process set forth in Scheme 5, the process forthe preparation of Formula (P)-I comprises contacting the compoundCPD-03 with MeNH(OMe)-HCl in the presence of a palladium catalyst, aphosphorus reagent, CO, and a base to form the compound

In some embodiments of forming CPD-15, the palladium catalyst isPd(OAc)₂.

In some embodiments of forming CPD-15, the phosphorus reagent isXantphos.

In some embodiments of forming CPD-15, the base is Na₂CO₃.

In some embodiments of the process for the preparation of Formula (P)-I,the process further comprises contacting the compound CPD-15 with MeMgXto obtain the compound

In some embodiments of the contacting the compound CPD-15, the MeMgX isselected from the group consisting of MeMgBr and MeMgCl.

In some embodiments of the contacting the compound CPD-15, the MeMgX isMeMgBr.

In some embodiments of the contacting the compound CPD-15, the MeMgX isMeMgCl.

In another embodiment of the process for the preparation of Formula(P)-I, the process further comprises contacting the compound CPD-15 witha chlorination reagent to form the compound

In some embodiments of the forming of CPD-16, the chlorination reagentis N-chlorosuccinimide.

In some embodiments, the forming of CPD-16 further comprises contactingCPD-15 with dichloroacetic acid.

In another embodiment of the process for the preparation of Formula(P)-I, the process further comprises contacting the compound CPD-16 withMeMgX to obtain the compound

In some embodiments of the contacting the compound CPD-16, the MeMgX isselected from the group consisting of MeMgBr and MeMgCl.

In some embodiments of the contacting the compound CPD-16, the MeMgX isMeMgBr.

In some embodiments of the contacting the compound CPD-16, the MeMgX isMeMgCl.

Also in accordance with Scheme 5, in another embodiment of the processfor the preparation of Formula (P)-I, the process further comprises thesteps of:

-   -   (a) contacting the compound CPD-03 with a vinyl tin reagent in        the presence of a palladium catalyst to form a mixture; and    -   (b) contacting the mixture of (a) with HCl    -   to form the compound

In some embodiments of forming CPD-17, the vinyl tin reagent is

In some embodiments of forming CPD-17, the palladium catalyst isPdCl₂(PPh₃)₂.

Also in accordance with the process set forth in Scheme 5, the processfor the preparation of Formula (P)-I comprises another method ofconverting CPD-03 to CPD-17. The process comprises contacting thecompound CPD-03 with butyl vinyl ether in the presence of a palladiumcatalyst, a phosphorus reagent, and a base to form the compound

In some embodiments of forming CPD-27, the palladium catalyst isPd(OAc)₂.

In some embodiments of forming CPD-27, the phosphorus reagent is1,1′-Ferrocenediyl-bis(diphenylphosphine) (dppf).

In some embodiments of forming CPD-27, the base is iPr₂NEt.

In some embodiments of the process for the preparation of Formula (P)-I,the process further comprises contacting the compound CPD-27 with anacid to form the compound

In some embodiments of forming CPD-17, the acid is HCl.

In some embodiments of the process for the preparation of Formula (P)-I,the process further comprises contacting the compound CPD-17 with achlorination reagent to form the compound

In some embodiments of the forming of CPD-18, the chlorination reagentis N-chlorosuccinimide.

In some embodiments, the forming of CPD-18 further comprises contactingCPD-17 with dichloroacetic acid.

In accordance with Scheme 5, whether the process proceeds via theformation of CPD-17 or CPD-15 as described supra the process for thepreparation of Formula (P)-I further comprises condensing the compoundCPD-18 with N,N-dimethyl-formamide dimethyl acetal to obtain thecompound

In some embodiments of the condensation of the compound CPD-18, whereinthe condensing further comprises L-proline.

In another embodiment of the process for the preparation of Formula(P)-I, the process further comprises contacting the compound CPD-19 with

in the presence of a base, and forming the compound

In some embodiments of forming the compound of CPD-20, the base isselected from the group consisting of K₂CO₃, N,N-diisopropylethylamine(DIPEA), triethylamine (TEA), tBuOK, tBuONa, and Cs₂CO₃.

In some embodiments of the forming of CPD-20, the base is K₂CO₃.

In another embodiment of the process for the preparation of Formula(P)-I, the process further comprises subjecting the compound CPD-20 to achromatographic separation to obtain the compound of Formula (P)-I.

In some embodiments of the process for the preparation of Formula (P)-I,the chromatographic separation comprises simulated moving bed (SMB)chromatography with a chiral stationary phase and a mobile phase.

In some embodiments of the process for the preparation of Formula (P)-I,the chiral stationary phase is selected from the group consisting ofChiralpak® AD, Chiralpak® AS, Chiralpak® AY, Chiralpak® AZ, Chiralpak®OD, Chiralpak® OZ, Chiralpak® IA, Chiralpak® IB-N, Chiralpak® IC,Chiralpak® ID, Chiralpak® IE, Chiralpak® IF, Chiralpak® IG, andChiralpak® IH.

In some embodiments of the process for the preparation of Formula (P)-I,the chiral stationary phase is Chiralpak® IB-N.

In some embodiments of the process for the preparation of Formula (P)-I,the mobile phase is selected from the group consisting of acetonitrile,methanol, acetonitrile and methanol, n-heptane and ethanol, n-heptaneand dichloromethane, n-heptane and ethylacetate, dichloromethane andmethanol, and dichloromethane and acetonitrile.

In some embodiments of the process for the preparation of Formula (P)-I,the mobile phase is dichloromethane and acetonitrile.

In some embodiments of the process for the preparation of Formula (P)-I,when the mobile phase is in the form of a mixture the mixtures may be ina volumetric ratio of about 1:1, about 2:1, about 3:1, about 4:1, about5:1, about 6:1, about 7:1, about 8:1, about 9:1, about 10:1, about 7:3,about 1:2, about 1:3, about 1:4, about 1:5, about 1:6, about 1:7, about1:8, about 1:9, about 1:10, about 3:7, or any ratio in between any tworatios.

A process for the preparation of the compound

comprising subjecting the compound

to chiral separation with a chiral amine and a solvent to obtain thecompound CPD-07.

In some embodiments of the chiral separation of the compound CPD-06, thechiral amine is selected from the group consisting of(S)-1-(naphthalen-2-yl)ethan-1-amine and(1S,2R)-2-amino-1,2-diphenylethan-1-ol.

In some embodiments of the chiral separation of the compound CPD-06, thechiral amine is (S)-1-(naphthalen-2-yl)ethan-1-amine.

In some embodiments of the chiral separation of the compound CPD-06, thechiral amine is (1S,2R)-2-amino-1,2-diphenylethan-1-ol.

In some embodiments of the chiral separation of the compound CPD-06, thesolvent is selected from the group consisting of toluene, ethylbenzene,n-butanol, anisole, DMSO, or a combination thereof.

In some embodiments of the chiral separation of the compound CPD-06, thesolvent is toluene.

In some embodiments of the chiral separation of the compound CPD-06, thesolvent is ethylbenzene.

In some embodiments of the chiral separation of the compound CPD-06, thesolvent is n-butanol.

In some embodiments of the chiral separation of the compound CPD-06, thesolvent is anisole.

In some embodiments of the chiral separation of the compound CPD-06, thesolvent is anisole and DMSO.

A process for the preparation of the compound

comprising subjecting the compound

to chiral separation with a chiral amine and a solvent to obtain thecompound CPD-12.

In some embodiments of the chiral separation of the compound CPD-11, thechiral amine is selected from the group consisting of(S)-1-(naphthalen-2-yl)ethan-1-amine and(1S,2R)-2-amino-1,2-diphenylethan-1-ol.

In some embodiments of the chiral separation of the compound CPD-11, thechiral amine is (S)-1-(naphthalen-2-yl)ethan-1-amine.

In some embodiments of the chiral separation of the compound CPD-11, thechiral amine is (1S,2R)-2-amino-1,2-diphenylethan-1-ol.

In some embodiments of the chiral separation of the compound CPD-11, thesolvent is selected from the group consisting of toluene, ethylbenzene,n-butanol, anisole, DMSO, or a combination thereof.

In some embodiments of the chiral separation of the compound CPD-11, thesolvent is toluene.

In some embodiments of the chiral separation of the compound CPD-11, thesolvent is ethylbenzene.

In some embodiments of the chiral separation of the compound CPD-11, thesolvent is n-butanol.

In some embodiments of the chiral separation of the compound CPD-11, thesolvent is anisole.

In some embodiments of the chiral separation of the compound CPD-11, thesolvent is anisole and DMSO.

Scheme 6 outlines another route of synthesizing a Formula (P)-I startingfrom CPD-03 utilizing a Sonogashira coupling. Chiral separation isutilized to produce Formula (P)-I.

In accordance with Scheme 6, some embodiments of the present applicationinvolves a process for the preparation of compound of Formula (P)-Ihaving the structure:

said process comprising:

-   -   subjecting

and propargyl alcohol to a Sonogashira coupling reaction in the presenceof a palladium catalyst and a base to form the compound

and converting CPD-21 to Formula (P)-I.

In some embodiments of the Sonogashira coupling of CPD-03, the palladiumcatalyst is Pd(PPh₃)₄.

In some embodiments of the Sonogashira coupling of CPD-03, the aminebase is triethylamine.

In some embodiments of the process for the preparation of Formula (P)-I,the process further comprises oxidizing the compound CPD-21 with anoxidizing agent to form the compound

In some embodiments of the oxidation of CPD-21, the oxidizing agent isDess-Martin periodinane.

In some embodiments of the process for the preparation of Formula (P)-I,the process further comprises comprising contacting the compound CPD-22with

in the presence of a base, and forming the compound

In some embodiments of the forming of CPD-23, the base is Na₂CO₃.

In some embodiments of the process for the preparation of Formula (P)-I,the process further comprises contacting the compound CPD-23 with achlorination reagent to form the compound

In some embodiments of the chlorination of CPD-23, the chlorinationreagent is N-chlorosuccinimide.

In some embodiments, the forming of CPD-20 further comprises contactingCPD-23 with dichloroacetic acid.

In some embodiments of the process for the preparation of Formula (P)-I,the process further comprises subjecting the compound CPD-20 to chiralchromatography to obtain the compound of Formula (P)-I.

Scheme 7 depicts another method of synthesizing CPD-17 starting fromCPD-03. CPD-03 utilized in this manner may be from any of theembodiments described herein that produce CPD-03. CPD-17 produced inthis manner may be used in any of the embodiments disclosed herein thatutilizes CPD-17.

Accordingly, some embodiments of the present application involve aprocess for the preparation of the compound

said method comprising contacting the compound

with Pd₂(dba)₃ and Zn(CN)₂ to form the compound

and converting CPD-24 to CPD-17.

In another embodiment of the process for the preparation of the compoundCPD-17, the process comprises contacting the compound CPD-24 with MeMgXto obtain the compound CPD-17.

In some embodiments of the contacting the compound CPD-17, the MeMgX isselected from the group consisting of MeMgBr, MeMgCl, and MeMgI.

In some embodiments of the contacting the compound CPD-17, the MeMgX isMeMgBr.

In some embodiments of the contacting the compound CPD-17, the MeMgX isMeMgCl.

In some embodiments of the contacting the compound CPD-17, the MeMgX isMeMgI.

Scheme 8 depicts another method of synthesizing CPD-04 starting fromCPD-02 via bromine containing intermediates. CPD-02 utilized in thismanner may be from any of the embodiments described herein that produceCPD-02. CPD-04 produced in this manner may be used in any of theembodiments disclosed herein that utilizes CPD-04.

In accordance with Scheme 8, some embodiments of the present applicationinvolve a process for the preparation of the compound

comprising contacting the compound

with HBr to form the compound

and converting CPD-25 to CPD-04.

In some embodiments of the process for the preparation of the compoundCPD-04, the process further comprises contacting the compound CPD-25with the compound

and a base to form the compound

In some embodiments, the base used to form CPD-26 is selected from thegroup consisting of K₂CO₃ and Cs₂CO₃.

In some embodiments, the base used to form CPD-26 is K₂CO₃.

In some embodiments, the base used to form CPD-26 is Cs₂CO₃.

In some embodiments of the process for the preparation of the compoundCPD-04, the process further comprises contacting the compound CPD-26with CO in the presence of a palladium catalyst, an amine base, andmethanol to form the compound

In some embodiments of the process for the preparation of the compoundCPD-26, the palladium catalyst is Pd(dppf)Cl₂•DCM.

In some embodiments of the process for the preparation of the compoundCPD-26, the amine base is triethylamine.

Scheme 9 depicts another method of synthesizing CPD-17 starting fromCPD-26. CPD-26 utilized in this manner may be from any of theembodiments described herein that produce CPD-26. CPD-17 produced inthis manner may be used in any of the embodiments disclosed herein thatutilizes CPD-17.

In accordance with Scheme 9, some embodiments of the present applicationinvolve a process for the preparation of the compound CPD-17 comprisingcontacting the compound CPD-26 with butyl vinyl ether in the presence ofa palladium catalyst, a phosphorus reagent, and a base to form thecompound

In some embodiments of forming CPD-27, the palladium catalyst isPd(OAc)₂.

In some embodiments of forming CPD-27, the phosphorus reagent is1,1′-Ferrocenediyl-bis(diphenylphosphine) (dppf).

In some embodiments of forming CPD-27, the base is iPr₂NEt.

In some embodiments of the process for the preparation of CPD-17, theprocess further comprises contacting the compound CPD-27 with an acid toform the compound

In some embodiments of forming CPD-17, the acid is HCl.

Scheme 10 depicts another method of synthesizing CPD-17 starting fromCPD-26. CPD-26 utilized in this manner may be from any of theembodiments described herein that produce CPD-26. CPD-17 produced inthis manner may be used in any of the embodiments disclosed herein thatutilizes CPD-17.

In accordance with Scheme 10, some embodiments of the presentapplication involve a process for the preparation of the compound CPD-17comprising the steps of:

-   -   (a) contacting the compound CPD-26 with hydroxyethyl vinyl ether        in the presence of a palladium catalyst, a phosphorus reagent,        and a base to form a mixture; and    -   (b) contacting the mixture of (a) with an acid to form the        compound

In some embodiments of forming CPD-17, the palladium catalyst isPd(OAc)₂.

In some embodiments of forming CPD-17, the phosphorus reagent is1,3-bis(diphenylphosphino)propane (dppp).

In some embodiments of forming CPD-17, the base is iPr₂NEt.

In some embodiments of forming CPD-17, the acid is HCl.

Scheme 11 depicts another method of synthesizing CPD-18 starting fromCPD-28. CPD-28 utilized in this manner may be from any of theembodiments described herein that produce CPD-28. CPD-18 produced inthis manner may be used in any of the embodiments disclosed herein thatutilizes CPD-18.

In accordance with Scheme 11, some embodiments of the presentapplication involve a process for the preparation of the compound CPD-18comprising the steps of:

-   -   (a) contacting the compound

with a vinyl tin reagent in the presence of a palladium catalyst to forma mixture; and

-   -   (b) contacting the mixture of (a) with an acid

-   -   to form the compound

In some embodiments of forming CPD-18, the vinyl tin reagent is

In some embodiments of forming CPD-18, the palladium catalyst isPd(dppf)Cl₂.

In some embodiments of forming CPD-18, the acid is HCl.

Scheme 12 depicts another method of synthesizing CPD-18 starting fromCPD-29. CPD-29 utilized in this manner may be from any of theembodiments described herein that produce CPD-29. CPD-18 produced inthis manner may be used in any of the embodiments disclosed herein thatutilizes CPD-18.

In accordance with Scheme 12, some embodiments of the presentapplication involve a process for the preparation of the compound CPD-18comprising contacting the compound CPD-28 with butyl vinyl ether in thepresence of a palladium catalyst, a phosphorus reagent, and a base toform the compound CPD-29

In some embodiments of forming CPD-18, the palladium catalyst isPd(OAc)₂.

In some embodiments of forming CPD-18, the phosphorus reagent is1,1′-Ferrocenediyl-bis(diphenylphosphine) (dppf).

In some embodiments of forming CPD-18, the base is iPr₂NEt.

In some embodiments of the process for the preparation of CPD-18, theprocess further comprises contacting the compound CPD-29 with an acid toform the compound

In some embodiments of forming CPD-18, the acid is HCl.

Scheme 13 depicts another method of synthesizing CPD-18 starting fromCPD-30. CPD-30 utilized in this manner may be from any of theembodiments described herein that produce CPD-30. CPD-18 produced inthis manner may be used in any of the embodiments disclosed herein thatutilizes CPD-18.

In accordance with Scheme 13, some embodiments of the presentapplication involve a process for the preparation of compound CPD-18comprising contacting the compound CPD-30 with butyl vinyl ether in thepresence of a palladium catalyst, a phosphorus reagent, and a base toform the compound CPD-29

In some embodiments of forming CPD-18, the palladium catalyst isPd(OAc)₂.

In some embodiments of forming CPD-18, the phosphorus reagent is1,1′-Ferrocenediyl-bis(diphenylphosphine) (dppf).

In some embodiments of forming CPD-18, the base is iPr₂NEt.

In some embodiments of the process for the preparation of CPD-18, theprocess further comprises contacting the compound CPD-29 with an acid toform the compound

In some embodiments of forming CPD-18, the acid is HCl.

Scheme 14 depicts another method of synthesizing CPD-18 starting fromCPD-30. CPD-30 utilized in this manner may be from any of theembodiments described herein that produce CPD-30. CPD-18 produced inthis manner may be used in any of the embodiments disclosed herein thatutilizes CPD-18.

In accordance with Scheme 14, some embodiments of the presentapplication involve a process for the preparation of the compound CPD-18comprising the steps of:

-   -   (a) contacting the compound

with hydroxyethyl vinyl ether in the presence of a palladium catalyst, aphosphorus reagent, and a base to form a mixture; and

-   -   (b) contacting the mixture of (a) with an acid to form the        compound

In some embodiments of forming CPD-17, the palladium catalyst isPd(OAc)₂.

In some embodiments of forming CPD-17, the phosphorus reagent is1,3-bis(diphenylphosphino)propane (dppp).

In some embodiments of forming CPD-17, the base is iPr₂NEt.

In some embodiments of forming CPD-17, the acid is HCl.

Scheme 15 depicts another method of synthesizing CPD-18 starting fromCPD-28. CPD-28 utilized in this manner may be from any of theembodiments described herein that produce CPD-28. CPD-18 produced inthis manner may be used in any of the embodiments disclosed herein thatutilizes CPD-18.

In accordance with Scheme 15, some embodiments of the presentapplication involve a process for the preparation of the compound CPD-18comprising the steps of:

-   -   (a) contacting the compound

with a vinyl tin reagent in the presence of a palladium catalyst to forma mixture; and

-   -   (b) contacting the mixture of (a) with an acid    -   to form the compound

In some embodiments of forming CPD-18, the vinyl tin reagent is

In some embodiments of forming CPD-18, wherein the palladium catalyst isPd(dppf)Cl₂.

In some embodiments of forming CPD-18, the acid is HCl.

Scheme 16 depicts another method of synthesizing CPD-05 starting fromCPD-28. CPD-28 utilized in this manner may be from any of theembodiments described herein that produce CPD-28. CPD-05 produced inthis manner may be used in any of the embodiments disclosed herein thatutilizes CPD-05.

In accordance with Scheme 16, some embodiments of the presentapplication involve a process for the preparation of the compound CPD-05comprising contacting the compound CPD-28 with CO in the presence of apalladium catalyst, an amine base, and methanol to form the compound

In some embodiments of forming CPD-05, the palladium catalyst isPd(dppf)Cl₂.

In some embodiments of forming CPD-05, the amine base is triethylamine.

Scheme 17 depicts another method of synthesizing CPD-05 starting fromCPD-30. CPD-30 utilized in this manner may be from any of theembodiments described herein that produce CPD-30. CPD-05 produced inthis manner may be used in any of the embodiments disclosed herein thatutilizes CPD-05.

In accordance with Scheme 17, some embodiments of the presentapplication involve a process for the preparation of the compound CPD-05comprising contacting the compound CPD-30 with CO in the presence of apalladium catalyst, a phosphorus reagent, an amine base, and methanol toform the compound CPD-05

In some embodiments of forming CPD-05, the palladium catalyst isPd(OAc)₂.

In some embodiments of forming CPD-05, the phosphorus reagent is1,1′-Ferrocenediyl-bis(diphenylphosphine) (dppf).

In some embodiments of forming CPD-05, the amine base is triethylamine.

Scheme 18 depicts another method of synthesizing CPD-16 starting fromCPD-28. CPD-28 utilized in this manner may be from any of theembodiments described herein that produce CPD-28. CPD-16 produced inthis manner may be used in any of the embodiments disclosed herein thatutilizes CPD-16.

In accordance with Scheme 18, some embodiments of the presentapplication involve a process for the preparation of the compound CPD-16comprising contacting the compound CPD-28 with MeNH(OMe)-HCl in thepresence of a palladium catalyst, a phosphorus reagent, CO, and a baseto form the compound

In some embodiments of forming CPD-16, the palladium catalyst isPd(OAc)₂.

In some embodiments of forming CPD-16, the phosphorus reagent isXantphos.

In some embodiments of forming CPD-16, the base is K₃PO₄.

Scheme 19 depicts another method of synthesizing CPD-16 starting fromCPD-30. CPD-30 utilized in this manner may be from any of theembodiments described herein that produce CPD-30. CPD-16 produced inthis manner may be used in any of the embodiments disclosed herein thatutilizes CPD-16.

In accordance with Scheme 19, some embodiments of the presentapplication involve a process for the preparation of the compound CPD-16comprising contacting the compound CPD-30 with MeNH(OMe)-HCl in thepresence of a palladium catalyst, a phosphorus reagent, CO, and a baseto form the compound

In some embodiments of forming CPD-16, the palladium catalyst isPd(OAc)₂.

In some embodiments of forming CPD-16, the phosphorus reagent isXantphos.

In some embodiments of forming CPD-16, the base is K₃PO₄.

Scheme 20 depicts another method of synthesizing CPD-11 starting fromCPD-26. CPD-26 utilized in this manner may be from any of theembodiments described herein that produce CPD-26. CPD-11 produced inthis manner may be used in any of the embodiments disclosed herein thatutilizes CPD-11.

In accordance with Scheme 20, some embodiments of the presentapplication involve a process for the preparation of the compound CPD-16that comprises the steps of:

-   -   (a) contacting the compound CPD-26 with CO in the presence of a        palladium catalyst, an amine base, a phosphorus reagent, and        MeOH/H₂O to form a mixture; and    -   (b) contacting the mixture of (a) with a base        to form the compound

In some embodiments of forming CPD-11, the palladium catalyst isPd(OAc)₂.

In some embodiments of forming CPD-11, the amine base is triethylamine.

In some embodiments of forming CPD-11, the phosphorus reagent is1,1′-Ferrocenediyl-bis(diphenylphosphine) (dppf).

In some embodiments of forming CPD-11, the base is NaOH.

Scheme 21 depicts another method of synthesizing CPD-06 starting fromCPD-28. CPD-28 utilized in this manner may be from any of theembodiments described herein that produce CPD-28. CPD-06 produced inthis manner may be used in any of the embodiments disclosed herein thatutilize CPD-06.

In accordance with Scheme 21, some embodiments of the presentapplication involve a process for the preparation of the compound CPD-06comprising contacting the compound CPD-28 with CO in the presence of apalladium catalyst, a base, and a solvent mixture to form the compoundCPD-06

In some embodiments of forming CPD-06, the palladium catalyst isPd(dppf)Cl₂.

In some embodiments of forming CPD-06, the base is Na₂CO₃.

In some embodiments of forming CPD-06, the base is K₂CO₃.

In some embodiments of forming CPD-06, the base is Li₂CO₃.

In some embodiments of forming CPD-06, the forming of CPD-06 furthercomprising contacting CPD-28 with triethylamine.

In some embodiments of forming CPD-06, the solvent mixture is MeOH/H₂O.

In some embodiments of forming CPD-06, the solvent mixture isacetonitrile/H₂O.

Scheme 22 depicts another method of synthesizing CPD-06 starting fromCPD-30. CPD-30 utilized in this manner may be from any of theembodiments described herein that produce CPD-30. CPD-06 produced inthis manner may be used in any of the embodiments disclosed herein thatutilizes CPD-06.

In accordance with Scheme 22, some embodiments of the presentapplication involve a process for the preparation of the compound CPD-06comprising contacting the compound CPD-30 with CO in the presence of apalladium catalyst, an amine base, a phosphorus reagent, a base, and DMFto form the compound CPD-06

In some embodiments of forming CPD-06, the palladium catalyst isPd(OAc)₂.

In some embodiments of forming CPD-06, the amine base is triethylamine.

In some embodiments of forming CPD-06, the phosphorus reagent is1,1′-Ferrocenediyl-bis(diphenylphosphine) (dppf).

In some embodiments of forming CPD-06, the base is K₂CO₃.

Scheme 23 depicts another method of synthesizing CPD-06 starting fromCPD-11. CPD-11 utilized in this manner may be from any of theembodiments described herein that produce CPD-11. CPD-06 produced inthis manner may be used in any of the embodiments disclosed herein thatutilizes CPD-06.

In accordance with Scheme 23, some embodiments of the presentapplication involve a process for the preparation of the compound CPD-06comprising contacting the compound CPD-11 with a chlorination reagent toform the compound

In some embodiments of forming CPD-06, the chlorination reagent isN-chlorosuccinimide.

In some embodiments, the forming of CPD-06 further comprises contactingCPD-11 with dichloroacetic acid.

Scheme 24 depicts another method of synthesizing CPD-15 starting fromCPD-26. CPD-26 utilized in this manner may be from any of theembodiments described herein that produce CPD-26. CPD-15 produced inthis manner may be used in any of the embodiments disclosed herein thatutilizes CPD-15.

In accordance with Scheme 24, some embodiments of the presentapplication involve a process for the preparation of the compound CPD-15comprising contacting the compound CPD-26 with MeNH(OMe)·HCl in thepresence of a palladium catalyst, a phosphorus reagent, CO, and a baseto form the compound

In some embodiments of forming CPD-15, the palladium catalyst isPd(OAc)₂.

In some embodiments of forming CPD-15, the phosphorus reagent isXantphos.

In some embodiments of forming CPD-15, the base is K₃PO₄.

Scheme 25 depicts another method of synthesizing CPD-30 starting fromCPD-26. CPD-26 utilized in this manner may be from any of theembodiments described herein that produce CPD-26. CPD-30 produced inthis manner may be used in any of the embodiments disclosed herein thatutilizes CPD-30.

In accordance with Scheme 25, some embodiments of the presentapplication involve a process for the preparation of the compound CPD-30comprising contacting the compound CPD-26 with a chlorination reagent toform the compound

In some embodiments of forming CPD-30, the chlorination reagent isN-chlorosuccinimide.

In some embodiments, the forming of CPD-30 further comprises contactingCPD-26 with dichloroacetic acid.

Scheme 26 depicts another method of synthesizing CPD-30 starting fromCPD-31. CPD-31 utilized in this manner may be from any of theembodiments described herein that produce CPD-31. CPD-30 produced inthis manner may be used in any of the embodiments disclosed herein thatutilizes CPD-30.

In accordance with Scheme 26, some embodiments of the presentapplication involve a process for the preparation of the compound CPD-30comprising contacting the compound CPD-31 with the compound

and a base to form the compound

In some embodiments, the base used to form CPD-30 is selected from thegroup consisting of K₂CO₃ and Cs₂CO₃.

In some embodiments, the base used to form CPD-30 is K₂CO₃.

In some embodiments, the base used to form CPD-30 is Cs₂CO₃.

Scheme 27 depicts another method of synthesizing CPD-31 starting fromCPD-25. CPD-25 utilized in this manner may be from any of theembodiments described herein that produce CPD-25. CPD-31 produced inthis manner may be used in any of the embodiments disclosed herein thatutilizes CPD-31.

In accordance with Scheme 27, some embodiments of the presentapplication involve a process for the preparation of the compound CPD-31comprising contacting the compound CPD-25 with a chlorination reagent toform the compound

In some embodiments of forming CPD-31, the chlorination reagent isN-chlorosuccinimide.

In some embodiments, the forming of CPD-31 further comprises contactingCPD-25 with dichloroacetic acid.

Scheme 28 depicts another method of synthesizing CPD-28 starting fromCPD-03. CPD-03 utilized in this manner may be from any of theembodiments described herein that produce CPD-03. CPD-28 produced inthis manner may be used in any of the embodiments disclosed herein thatutilizes CPD-28.

In accordance with Scheme 28, some embodiments of the presentapplication involve a process for the preparation of the compound CPD-28comprising contacting the compound CPD-03 with a chlorination reagent toform the compound

In some embodiments of forming CPD-28, the chlorination reagent isN-chlorosuccinimide.

In some embodiments, the forming of CPD-28 further comprises contactingCPD-03 with dichloroacetic acid.

Some embodiments of the present application describe a process for thepreparation of TAUT-01 having the structure:

-   -   comprising:    -   contacting the compound

with the compound

in the presence of dimethylacetemide (DMAc) to form the compoundTAUT-01.

Some embodiments are directed a method of obtaining the single orenriched atropisomers of CPD-02, said method comprising subjectingCPD-02 to a chromatographic separation to obtain

In some embodiments of obtaining the single or enriched atropisomers ofCPD-02, the chromatographic separation comprises simulated moving bed(SMB) chromatography with a chiral stationary phase and a mobile phase.

In some embodiments of obtaining the single or enriched atropisomers ofCPD-02, the chiral stationary phase is selected from the groupconsisting of Chiralpak® AD, Chiralpak® AS, Chiralpak® AY, Chiralpak®AZ, Chiralpak® OD, Chiralpak® OZ, Chiralpak® IA, Chiralpak® IB-N,Chiralpak® IC, Chiralpak® ID, Chiralpak® IE, Chiralpak® IF, Chiralpak®IG, and Chiralpak® IH.

In some embodiments of obtaining the single or enriched atropisomers ofCPD-02, the chiral stationary phase is Chiralpak® IB-N.

In some embodiments of obtaining the single or enriched atropisomers ofCPD-02, the mobile phase is selected from the group consisting ofacetonitrile, methanol, acetonitrile and methanol, n-heptane andethanol, n-heptane and dichloromethane, n-heptane and ethylacetate,dichloromethane and methanol, and dichloromethane and acetonitrile.

In some embodiments of obtaining the single or enriched atropisomers ofCPD-02, the mobile phase is dichloromethane and acetonitrile.

Some embodiments are directed a method of obtaining the single orenriched atropisomers of CPD-03, said method comprising subjectingCPD-03 to a chromatographic separation to obtain

In some embodiments of obtaining the single or enriched atropisomers ofCPD-03, the chromatographic separation comprises simulated moving bed(SMB) chromatography with a chiral stationary phase and a mobile phase.

In some embodiments of obtaining the single or enriched atropisomers ofCPD-03, the chiral stationary phase is selected from the groupconsisting of Chiralpak® AD, Chiralpak® AS, Chiralpak® AY, Chiralpak®AZ, Chiralpak® OD, Chiralpak® OZ, Chiralpak® IA, Chiralpak® IB-N,Chiralpak® IC, Chiralpak® ID, Chiralpak® IE, Chiralpak® IF, Chiralpak®IG, and Chiralpak® IH.

In some embodiments of obtaining the single or enriched atropisomers ofCPD-03, the chiral stationary phase is Chiralpak® IB-N.

In some embodiments of obtaining the single or enriched atropisomers ofCPD-03, the mobile phase is selected from the group consisting ofacetonitrile, methanol, acetonitrile and methanol, n-heptane andethanol, n-heptane and dichloromethane, n-heptane and ethylacetate,dichloromethane and methanol, and dichloromethane and acetonitrile.

In some embodiments of obtaining the single or enriched atropisomers ofCPD-03, the mobile phase is dichloromethane and acetonitrile.

Some embodiments are directed a method of obtaining the single orenriched atropisomers of CPD-20, said method comprising subjectingCPD-20 to a chromatographic separation to obtain

In some embodiments of obtaining the single or enriched atropisomers ofCPD-20, the chromatographic separation comprises simulated moving bed(SMB) chromatography with a chiral stationary phase and a mobile phase.

In some embodiments of obtaining the single or enriched atropisomers ofCPD-20, the chiral stationary phase is selected from the groupconsisting of Chiralpak® AD, Chiralpak® AS, Chiralpak® AY, Chiralpak®AZ, Chiralpak® OD, Chiralpak® OZ, Chiralpak® IA, Chiralpak® IB-N,Chiralpak® IC, Chiralpak® ID, Chiralpak® IE, Chiralpak® IF, Chiralpak®IG, and Chiralpak® IH.

In some embodiments of obtaining the single or enriched atropisomers ofCPD-20, the chiral stationary phase is Chiralpak® IB-N.

In some embodiments of obtaining the single or enriched atropisomers ofCPD-20, the mobile phase is selected from the group consisting ofacetonitrile, methanol, acetonitrile and methanol, n-heptane andethanol, n-heptane and dichloromethane, n-heptane and ethylacetate,dichloromethane and methanol, and dichloromethane and acetonitrile.

In some embodiments of obtaining the single or enriched atropisomers ofCPD-20, the mobile phase is dichloromethane and acetonitrile.

In any of the foregoing, when the mobile phase is in the form of amixture the mixtures may be in a volumetric ratio of about 1:1, about2:1, about 3:1, about 4:1, about 5:1, about 6:1, about 7:1, about 8:1,about 9:1, about 10:1, about 7:3, about 1:2, about 1:3, about 1:4, about1:5, about 1:6, about 1:7, about 1:8, about 1:9, about 1:10, about 3:7,or any ratio in between any two ratios.

In some embodiments of the present application, the salts disclosedherein may be co-crystals.

Some embodiments of the present application relate to a compound, or asalt thereof, or a co-crystal thereof, selected from the groupconsisting of:

Experimental Section

The compound of the present invention can, but are not limited to beingprepared using the methods illustrated in the experimental proceduresdetailed below. The starting materials used to prepare the compounds ofthe present invention are commercially available or can be preparedusing routine methods known in the art. Solvents and reagents, whosesynthetic preparations are not described below, can be purchased atSigma-Aldrich or Fisher Scientific.

Representative procedures for the preparation of compounds of thisdisclosure are outlined below.

Example 1: General Resolution Screening Procedure

A stock solution of the racemate was made in pure MeOH or, in case oflow solubility, in a mixture of MeOH and CHCl₃. 15 μmol of racemate waspipetted in 96 tube plates. To these solutions stock solutions of theresolving agents (24 basic or 36 acidic resolving agents) were added,each containing 15 μmol of resolving agent (or 7.5 μmol in case of halfan equivalent of some double acids). The transfer solvents were allowedto evaporate in a circulation oven at 45° C. for two days. The drysolids were treated with 0.5 mL of the 8 solvent systems. The tubes werecapped and heated to 70° C. for 15 minutes whilst being sonicated. Theresulting mixtures were allowed to cool to RT over a couple of days. Atleast one and a maximum of two samples per resolving agents were workedup. The suspension was filtered and the solid and filtrate were eachdissolved in MeOH (1.5 mL) and analyzed by chiral HPLC or chiral UPC assuch. If the filtrate contained water, it was first concentrated todryness with a flow of N₂ at 50° C. before the MeOH was added as thechiral methods are not compatible with water. The optical purities ofsolid and filtrate of a given experiment were used to determine theyield. Results of various resolving agents for isolating CPD-07 areshown in Table 1, entries A and B are further elaborated in Examples 9and 10. Results of various resolving agents for isolating Formula P-(I).

The yield of precipitated material was calculated as follows:

${{Crystallization}{yield}} = {{- \frac{{ee}_{soln} - {ee}_{0}}{{ee}_{cryst} - {ee}_{soln}}} \times 100\%}$

In which:

-   -   ee_(soln)=Optical purity of the solution    -   ee₀=Optical purity of the material before the resolution        -   ee_(cryst)=Optical purity of the precipitated material

TABLE 1 Screening Results for isolating CPD-07 ee ee calc. EntryResolving agent Solvent solid^(a) filtrate^(a) yield A(S)-1-(naphthalen-2-yl)ethan-1- EtOH 99.86% amine B(1S, 2R)-2-amino-1,2-diphenylethan- MeCN 99.19% 1-ol 1(S)-2-amino-1-propanol (L-alaninol) MeCN    -7%  +5% 40% 2(S)-2-amino-1-propanol (L-alaninol) MEK    -6%  +7% 55% 3(R)-(+)-1-Phenylethylamine MeCN    -5%  +5% 46% 4(R)-(+)-1-phenylethylamine EtOH Racemic  -6% — 5 L-(-)-2-amino-1-butanolMeCN Racemic -37% — 6 L-(-)-2-amino-1-butanol IPA Racemic -20% — 7(1R, 2S)-(-)-ephedrine MeCN    -6% Racemic — 8 (1R, 2S)-(-)-ephedrineEtOH   +26% -24% 48% 9 (S)-(+)-2-amino-3-methyl-1-butanol MeCN    -8% +6% 43% (L-valinol) 10 (S)-(+)-2-amino-3-methyl-1-butanol IPA    -5%Racemic — (L-valinol) 11 (S)-(-)-N-benzyl-α- iPrOAc    -7% Racemic —methylbenzylamine 12 (+)-dehydroabietylamine (60%  H₂O   -25% +11% 30%purity) 13 (+)-dehydroabietylamine (60%  MeCN   -51%  +5%  9% purity) 14(1S,2S)-(+)-2-amino-1-phenyl-1,3- H₂O Racemic  -7% — propanediol 15(R)-(+)-3-pyrrolidinol MeCN Racemic -19% — 16 (R)-(+)-3-pyrrolidinol MEKRacemic  -9% — 17 (S)-(+)-2-pyrrolidinemethanol MeCN Racemic -10% —(L-prolinol) 18 (S)-(+)-2-pyrrolidinemethanol IPA   -15% +34% 69%(L-prolinol) 19 (S)-(-)-1-(1-naphthyl)ethylamine MeCN   -15% +17% 52% 20(S)-(-)-1-(1-naphthyl)ethylamine IPA Racemic  -8% — 21(R)-1-amino-2-propanol MeCN Racemic  -9% — 22 (R)-1-amino-2-propanol MEK  -20% +33% 62% 23 L-proline amide MEK    -6% +12% 67% 24L-proline amide Dioxane Racemic -34% — 25 (1R,2R)-(-)-pseudoephedrineMeCN Racemic  -6% — 26 (1R,2R)-(-)-pseudoephedrine EtOH Racemic Racemic— 27 L-phenylalaninol IPA Racemic  -5% — 28 (1R,2R)-2-amino-1-(4- IPA   -8% Racemic — nitrophenyl)propane-1,3-diol 29 cinchonine MeCN    -6%Racemic — 30 cinchonine iPrOAc   -17% Racemic — 31 quinidine iPrOAcRacemic  -6% — 32 quinine Dioxane Racemic -16% — 33 cinchonidine iPrOAcRacemic -33% — 34 (R)-(-)-2-phenylglycine amide MeCN Racemic -22% — 35(R)-(-)-2-phenylglycine amide MEK Racemic -10% — 36(R)-(+)-2-phenylpropylamine MeCN Racemic -17% —

TABLE 2 Screening Results for isolating Formula P-(I) ee  calc EntryResolving agent Solvent ee solid^(a) filtrate^(a) yield 1dibenzoyl-L-tartaric acid IPA Racemic Racemic — hydrate (1 eq) 2(R)-phencyphos hydrate MeCN Racemic Racemic — (1 eq) 3(R)-phencyphos hydrate 1:1 Racemic Racemic — (1 eq) H₂O:EtOH 4(R)-chlocyphos (1 eq) MeCN Racemic Racemic — 5 (R)-chlocyphos (1 eq) IPARacemic Racemic — 6 (-)-tartaric acid (1 eq) 1:1 Racemic Racemic —H₂O:EtOH 7 (+)-camphorsulfonic acid 1:1 Racemic Racemic — (1 eq)H₂O:EtOH 8 (+)-camphorsulfonic acid iPrOAc Racemic Racemic — (1 eq) 9D-camphoric acid (1 eq) 1:1 Racemic Racemic — H₂O:EtOH 10D-camphoric acid (1 eq) iPrOAc Racemic Racemic — 11 L-malic acid (1 eq)1:1 Racemic Racemic — H₂O:EtOH 12 L-malic acid (1 eq) iPrOAc RacemicRacemic — 13 (S)-mandelic acid (1 eq) 1:1 Racemic Racemic — H₂O:EtOH 14(S)-mandelic acid (1 eq) EtOH Racemic Racemic — 15L-(-)-di-p-anisoyltartaric acid  1:1 Racemic Racemic — (1 eq) H₂O:EtOH16 L-(-)-di-p-toluoyltartaric acid  IPA Racemic Racemic — (1 eq) 17(R)-anisyphos (1 eq) 1:1 Racemic Racemic — H₂O:EtOH 18(R)-anisyphos (1 eq) IPA Racemic Racemic — 19 (R)-BINAP phosphate (1 eq)iPrOAc Racemic Racemic — 20 (R)-(-)-2-chloromandelic 1:1 Racemic Racemic— acid (1 eq) H₂O:EtOH 21 N-acetyl-L-phenylalanine  IPA Racemic Racemic— (1 eq) 22 N-acetyl-D-leucine (1 eq) 1:1 Racemic Racemic H₂O:EtOH 23N-acetyl-D-leucine (1 eq) iPrOAc Racemic Racemic — 24(R)-(-)-2-phenylpropionic 1:1 Racemic Racemic — acid (1 eq) H₂O:EtOH 25(R)-(-)-2-phenylpropionic IPA Racemic Racemic — acid (1 eq) 26(S)-naproxen (1 eq) 1:1 Racemic Racemic — H₂O:EtOH 27(S)-naproxen (1 eq) IPA Racemic Racemic — 28 D-(+)-3-phenyllactic acid1:1 Racemic Racemic — (1 eq) H₂O:EtOH 29 D-(+)-3-phenyllactic acid IPARacemic Racemic — (1 eq) 30 N-acetyl-L-proline (1 eq) H₂O RacemicRacemic — 31 N-acetyl-L-proline (1 eq) IPA Racemic Racemic — 32L-α-hydroxyisovaleric acid 1:1 Racemic Racemic — (1 eq) H₂O:EtOH 33L-α-hydroxyisovaleric acid iPrOAc Racemic Racemic — (1 eq) 34dibenzoyl-L-tartaric acid EtOH Racemic Racemic — hydrate (0.5 eq) 35(-)-tartaric acid (0.5 eq) 1:1 Racemic Racemic — H₂O:EtOH 36(-)-tartaric acid (0.5 eq) IPA Racemic Racemic — 37L-(-)-di-p-anisoyltartaric acid 1:1 Racemic Racemic — (0.5 eq) H₂O:EtOH38 L-(-)-di-p-anisoyltartaric acid IPA Racemic Racemic — (0.5 eq) 39L-(-)-di-p-toluoyltartaric acid 1:1 Racemic Racemic — (0.5 eq) H₂O:EtOH40 L-(-)-di-p-toluoyltartaric acid IPA Racemic Racemic — (0.5 eq) 41(2S,3S)-2'-methoxytartranilic MeCN Racemic Racemic — acid (1 eq) 42(2S,3S)-2'-methoxytartranilic 1:1 Racemic Racemic — acid (1 eq) H₂O:EtOH43 (R)-phenylsuccinic acid 1:1 Racemic Racemic — (1 eq) H₂O:EtOH 44(R)-phenylsuccinic acid (1 eq) iPrOAc Racemic Racemic — 45(S)-(α-methylbenzyl) 1:1 Racemic Racemic — phthalamic acid (1 eq)H₂O:EtOH 46 (S)-(α-methylbenzyl) IPA Racemic Racemic —phthalamic acid (1 eq) 47 (S)-4-bromomandelic acid 1:1 Racemic Racemic —(1 eq) H₂O:EtOH 48 (S)-4-bromomandelic acid iPrOAc Racemic Racemic —(1 eq) 49 Boc-D-phenylalanine (1 eq) 1:1 Racemic Racemic — H₂O:EtOH 50Boc-D-phenylalanine (1 eq) IPA Racemic Racemic — 51(2R,3R)-2'-chlorotartranilic 1:1 Racemic Racemic — acid (1 eq) H₂O:EtOH52 (2R,3R)-2'-chlorotartranilic IPA Racemic Racemic — acid (1 eq) 53Boc-D-homophenylalanine 1:1 Racemic Racemic — (1 eq) H₂O:EtOH 54Boc-D-homophenylalanine IPA Racemic Racemic — (1 eq) 55(S)-O'-acetyl mandelic acid IPA Racemic Racemic — (1 eq) 56D-pyroglutamic acid (1 eq) 1:1 Racemic Racemic H₂O:EtOH 57D-pyroglutamic acid (1 eq) IPA Racemic Racemic — 58(2R,3R)-tartranilic acid (1 eq) 1:1 Racemic Racemic — H₂O:EtOH 59(2R,3R)-tartranilic acid (1 eq) MEK Racemic Racemic — 60(R)-4-methylmandelic acid 1:1 Racemic Racemic — (1 eq) H₂O:EtOH 61(R)-4-methylmandelic acid iPrOAc Racemic Racemic — (1 eq) 62(R)-α-methoxy-phenylacetic 1:1 Racemic Racemic — acid (1 eq) H₂O:EtOH 63(R)-α-methoxy-phenylacetic iPrOAc Racemic Racemic — acid (1 eq)

Example 2: Preparation of3-acetyl-2′-chloro-4-hydroxy-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one(CPD-01)

To a round bottom flask with a short path distillation head with areceiving flask was added 2-Chloro-5-methyl pyridine-4-amine (SM-01)(42.0 kg, 1.0 eq), 2,2,6-trimethyl-4H-1,3-dioxin-4-one (SM-02) (3.7 eq.)and DMAc (5.0 vol.). The reaction mass was slowly warmed to 115-120° C.,and the reaction mass was maintained at that temperature for 4-6 hours.(Note: Acetone was collected in a receiving flask during thisoperation). The reaction was monitored by TLC and HPLC. After thereaction was completed, the mass was cooled to 50-60° C. Water (15.0vol.) was slowly added into the reaction mass at 50-60° C. The mass wasthen cooled first to 25-30° C. and then to 5-10° C. After stirring for1-2 hrs. the solids were filtered and washed with cold water (15.0vol.). The solid was dried in a hot air oven to afford 79.5 kg (yield:92.3%) of3-acetyl-2′-chloro-4-hydroxy-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-onewith HPLC purity 96.45%. ¹H-NMR (400 MHz, DMSO-d₆): δ ppm 15.74 (s, 1H),8.52 (s, 1H), 7.67 (s, 1H), 6.25 (s, 1H), 2.55 (s, 3H), 2.02 (s, 3H),1.94 (s, 3H). MS (ES) m/z 293.62 (M+H).

Example 3: Preparation of2′-chloro-4-hydroxy-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one (CPD-02)

To a round bottom flask was added3-acetyl-2′-chloro-4-hydroxy-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one(CPD-01, Example 2) (65 kg, 1.0 eq), water (12.0 vol.), and IPA·HCl(20-25% solution) (3.5 vol.) at 25-30° C. The reaction mass was heatedto 80-85° C. and maintained for 14-15 hours at this temperature. Thereaction was monitored by TLC. After reaction was completed, thereaction mass was cooled to 5-10° C. and stirred for 2-3 hours. Thesolids were filtered, washed with cold water, and dried for 1-2 hours.The material was then dried at 50-55° C. in an oven to afford 63.3 kg(yield: 72.3%) of2′-chloro-4-hydroxy-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one with HPLCpurity 83.7%. ¹H-NMR (400 MHz, DMSO-d₆): δ ppm 10.8 (br s, 1H), 8.47 (s,1H), 7.55 (s, 1H), 5.97-5.96 (m, 1H), 5.57 (d, J=2.4 Hz, 1H), 1.96 (s,3H), 1.83 (s, 3H). MS (ES) m/z 251.52 (M+H).

Example 4: Preparation of 2-chloromethyl-3,5-difluoro-pyridine (INT-01)

Step A: Preparation of 3,5-difluoro-pyridine-2-carboxylic Acid EthylEster

To a cooled suspension (using an ice water bath) of3,5-difluoropyridine-2-carboxylic acid (2.0 g, 12.6 mmol) in ethanol (5mL), was added thionyl chloride (2 mL) in a dropwise manner. Thesolution was then heated to 60° C. for 3 h. The reaction was cooled toambient temperature and was concentrated in vacuo to provide the ethylester, hydrochloride salt as a yellow oil (2.5 g).

Step B: Preparation of (3,5-difluoro-pyridin-2-yl)-methanol

To a cooled (using an ice water bath) solution of3,5-difluoro-pyridine-2-carboxylic acid ethyl ester of part A (2.5 g,12.6 mmol) in ethanol (10 mL) was added sodium borohydride (1.43 g, 37.8mmol) in a portion wise manner. The solution was stirred at 0° C. forthirty minutes and at ambient temperature for 2 h. The reaction mixturewas cooled to 0° C. and saturated ammonium chloride was added dropwise.The solvent was removed in vacuo, and the resulting residue waspartitioned between ethyl acetate and water. The organic layer waswashed with saturated ammonium chloride, water, and brine, and driedover magnesium sulfate. The slurry was filtered and concentrated toprovide the alcohol as a yellow oil (1.8 g): MS (ES) m/e 146 (M+H).

Step C: Preparation of 2-chloromethyl-3,5-difluoro-pyridine

To a solution of (3,5-difluoro-pyridin-2-yl)-methanol from part B (1.8g, 12.3 mmol) in dichloromethane (20 mL) was added three drops ofN,N-dimethylformamide and cooled using an ice water bath. Thionylchloride (2 mL) was added dropwise and the solution was stirred atambient temperature for one hour. The solution was concentrated in vacuoto provide the chloro compound as a light brown liquid (1.75 g).

Example 5: Preparation of2′-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one(CPD-03)

To a stirred solution of2′-chloro-4-hydroxy-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one (CPD-02,Example 3) (200.0 g, 1.0 eq.), in DMF (4 vol.) was added K₂CO₃ (1.5 eq.)at RT. It was stirred for 10-15 min. and then2-(chloromethyl)-3,5-difluoro-pyridine (INT-01, Example 4) (1.2 eq.) inDMF (1 vol.) was added slowly at 25-35° C. The reaction mass was stirredfor 16-18 h at 25-35° C. Progress of the reaction was monitored by TLCand IPC-HPLC. After completion of the reaction (Not More Than (NMT) 5.0%a/a), ice-cold water (20 vol.) was charged. The mixture was stirred for1 h, and it was then extracted with EtOAc (3×10 vol.). The combinedEtOAc layer was washed with water (1×5 vol.) and brine solution (1×5vol.), and then it was dried over anhydrous Sodium sulphate. The EtOAclayer was distilled-off under reduced pressure at 45-50° C. MTBE wasadded (1-2 vol.) and the mixed solvent was co-distilled. Additional MTBE(3 vol.) was added at 25-35° C. to precipitate the solid. Afterfiltration, the wet solid was dried under reduced pressure at 45-50° C.to afford 244 g (yield: 80.9%) of2′-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-onewith HPLC purity 96.45%. ¹H-NMR (400 MHz, DMSO-d₆): δ ppm 8.58 (d, 1H,J=2.4 Hz); 8.49 (s, 1H); 8.03-8.10 (m, 1H), 7.60 (s, 1H), 6.11-6.14 (m,1H), 6.02 (d, 1H, J=2.4 Hz), 5.24 (d, 2H, J=1.6 Hz), 1.98 (s, 3H), 1.85(s, 3H), MS (ES) m/z 378.19 (M+H).

Example 6: Preparation of Methyl4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2-oxo-2H-[1,4′-bipyridine]-2′-carboxylate(CPD-04)

To a stirred suspension of2′-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one(CPD-03, Example 5) (100.0 g, 1.0 eq.) in methanol (8 vol.), was addedtriethylamine (TEA (3.0 eq.). The reaction was purged with argon gas for30 min. Then the reaction mass was transferred into an autoclave underargon atmosphere and Pd(dppf)Cl₂ (0.05 eq.) was added. The reactor waspressurized with CO gas (15 PSI (1 Kg)). The pressure was released andthe reactor was re-pressurized with CO pressure (75 PSI (5 Kg)). Thetemperature was raised to 95-100° C. and maintained for 16 h. Progressof the reaction was monitored by TLC. After completion of reaction, thereaction mass was cooled to 25-35° C. The pressure was released and thereactor was purged with nitrogen. The contents of the reactor werefiltered through a Celite bed. The filtrate was distilled under reducedpressure at below 45° C. and co-distilled with EtOAc (1-2 vol.). A crudesolid was obtained. It was diluted with EtOAc (5 vol.) and was stirredfor 1-2 h at 25-35° C. The mixture was filtered to afford 85 g (yield:80%) of Methyl4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2-oxo-2H-[1,4′-bipyridine]-2′-carboxylatewith HPLC purity 99.37%. ¹H-NMR (400 MHz, DMSO-d₆): δ ppm 8.78 (s, 1H),8.59 (d, 1H, J=2.4 Hz), 8.04-8.11 (m, 1H), 7.90 (s, 1H), 6.12-6.15 (m,1H), 6.03 (d, 1H, J=2.4 Hz), 5.24 (d, 2H, J=1.6 Hz), 3.88 (s, 3H), 2.09(s, 3H), 1.81 (s, 3H); MS (ES) m/z 402.44 (M+H).

Example 7: Preparation of Methyl3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2-oxo-2H-[1,4′-bipyridine]-2′-carboxylate(CPD-05)

To a stirred suspension of Methyl4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2-oxo-2H-[1,4′-bipyridine]-2′-carboxylate(CPD-04, Example 6) (100.0 g, 1.0 eq.) in IPA (15.0 vol.) was addeddichloroacetic acid (0.25 eq.) at 25-35° C. Slowly, the temperature wasraised to 45-50° C. and N-chlorosuccinimide (0.95 eq.) was added. Thenthe temperature was raised to 60-65° C., and it was maintained for 1 h.Progress of the reaction was monitored by TLC. After completion ofreaction, the heating was stopped and the reaction mass was allowed tocool to 25-35° C., and then to 0-5° C. The solid was filtered and washedwith IPA. The wet solid was dried at 45-50° C., to afford 70 g (yield:64.5%) Methyl3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2-oxo-2H-[1,4′-bipyridine]-2′-carboxylatewith HPLC purity 96.46%. ¹H-NMR (400 MHz, DMSO-d₆): δ ppm 8.82 (s, 1H),8.60 (d, 1H, J=2.4 Hz), 8.07-8.13 (m, 1H), 8.03 (s, 1H), 6.79 (d, 1H,J=0.4 Hz), 5.47 (d, 2H, J=1.2 Hz), 3.89 (s, 3H), 2.08 (s, 3H), 1.92 (s,3H), MS (ES) m/z 436.36 (M+H).

Example 8: Preparation of3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2-oxo-2H-[1,4′-bipyri-dine]-2′-carboxylicacid (CPD-06)

To a stirred solution of Methyl3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2-oxo-2H-[1,4′-bipyridine]-2′-carboxylate(CPD-05, Example 7) (34 g, 1.0 eq.) in THF (5 vol.) was added LiOH·H₂O(3.0 eq.) in water (5 vol.) at 25-35° C. The mixture was then stirredfor 2-4 h. After completion of the reaction, EtOAc (5.0 vol.) was added.After stirring for 10-15 min., the aqueous layer and the organic layerswere separated. The pH of the aqueous was adjusted to 3-5 with dil. HCl(4M solution) at 25-35° C. The solid was filtered and washed withn-heptane (2-3 vol.). The obtained wet solid was dried at 45-50° C. for3-4 h to afford 23.0 g (yield: 70.0%) of3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2-oxo-2H-[1,4′-bipyri-dine]-2′-carboxylicacid with HPLC purity 97.93%, Chiral HPLC purity, Isomer 1: Isomer 2(48.75%:51.25%). ¹H-NMR (400 MHz, DMSO-d6): δ ppm 13.35 (br s, 1H), 8.80(s, 1H), 8.60 (d, 1H, J=2.4 Hz), 8.01-8.13 (m, 1H), 7.97 (s, 1H), 6.79(s, 1H), 5.47 (d, 2H, J=1.6 Hz), 2.08 (s, 3H), 1.92 (s, 3H), MS (ES) m/z422.36 (M+H).

Example 9: Preparation of(P)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2-oxo-2H-[1,4′-bipyri-dine]-2′-carboxylicacid (CPD-07) via chiral separation with(S)-1-(naphthalen-2-yl)ethan-1-amine

Step 1: Synthesis of(P)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2-oxo-2H-[1,4′-bipyridine]-2′-carboxylate(S)-1-(naphthalen-2-yl)ethan-1-aminium (Isomer 1 Salt A)

Step 1: To a stirred suspension of3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2-oxo-2H-[1,4′-bipyri-dine]-2′-carboxylicacid (CPD-06, Example 8, Isomer 1: Isomer 2, 48.75%:51.25%) (10 g, 1.0eq.) in ethanol (200 mL, 20 vol.) (250 mL RBF) was added 0.9 eq. of(S)-1-(naphthalen-2-yl)ethan-1-amine at 60-65° C. (Observation: Afteraddition of (S)-1-(naphthalen-2-yl)ethan-1-amine, a clear solution wasobserved). Then stirring was continued at 60-65° C. for 1-2 h. Thestirred solution was allowed to cool to 25-35° C. for 24 h. The solidwas filtered to afford 15 g of(P)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2-oxo-2H-[1,4′-bipyri-dine]-2′-carboxylate(S)-1-(naphthalen-2-yl)ethan-1-aminium (Isomer 1 Salt A) with enhancedHPLC chiral purity (Isomer 1: Isomer 2, 55.36%:44.64%). ¹H-NMR (400 MHz,DMSO-d₆): δ ppm 8.58-8.62 (m, 2H), 8.58-8.62 (m, 2H), 8.04-8.14 (m, 1H),7.82-8.02 (m, 4H), 7.72 (s, 1H), 7.62-7.70 (m, 1H), 7.45-7.57 (m, 2H),6.11-6.14 (m, 1H), 6.77 (s, 1H), 5.45 (d, 2H, J=10.8 Hz), 4.43-4.55 (m,1H), 2.04 (s, 3H), 2.00 (s, 3H), 1.45-1.60 (m, 3H); MS (ES) m/z 422(M+H).

Step 2: First purification of(P)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2-oxo-2H-[1,4′-bipyridine]-2′-carboxylate(S)-1-(naphthalen-2-yl)ethan-1-aminium (Isomer 1 Salt A). The wet solid,(P)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2-oxo-2H-[1,4′-bipyridine]-2′-carboxylate(S)-1-(naphthalen-2-yl)ethan-1-aminium (Isomer 1 Salt A), (Example 9,Step 1, 15 g, Isomer 1: Isomer 2, 55.36%:44.64) in methanol (10 vol.)was heated with stirring to 60-65° C. for 1-2 h to afford a clearsolution. Then the heating was stopped and the solution was allowed tocool to 25-35° C. The mixture was stirred for 24 h and filtered. Thisafforded 11.5 g of(P)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2-oxo-2H-[1,4′-bipyridine]-2′-carboxylate(S)-1-(naphthalen-2-yl)ethan-1-aminium with enhanced HPLC chiral purity(Isomer 1: Isomer 2, 83.06%:16.94%).

Step 3: Second purification of(P)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2-oxo-2H-[1,4′-bipyridine]-2′-carboxylate(S)-1-(naphthalen-2-yl)ethan-1-aminium (Isomer 1 Salt A). The wet solid,(P)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2-oxo-2H-[1,4′-bipyridine]-2′-carboxylate(S)-1-(naphthalen-2-yl)ethan-1-aminium (Isomer 1 Salt A), (Example 9,Step 2, 11.5 g, Isomer 1: Isomer 2, 83.06%:16.94%) in methanol (10 vol.)was heated to 60-65° C. with stirring for 1-2 h. Then the heating wasstopped and the solution was allowed to cool to 25-35° C. The mixturewas stirred for 24 h and then filtered. This afforded 8.9 g of(P)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2-oxo-2H-[1,4′-bipyridine]-2′-carboxylate(S)-1-(naphthalen-2-yl)ethan-1-aminium (Isomer 1 Salt A) with enhancedHPLC chiral purity (Isomer 1: Isomer 2, 92.48%:7.52%).

Step 4: Third purification of(P)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2-oxo-2H-[1,4′-bipyridine]-2′-carboxylate(S)-1-(naphthalen-2-yl)ethan-1-aminium (Isomer 1 Salt A). The wet solid,(P)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2-oxo-2H-[1,4′-bipyridine]-2′-carboxylate(S)-1-(naphthalen-2-yl)ethan-1-aminium (Isomer 1 Salt A), (Example 9,Step 3, 8.9 g, Isomer 1: Isomer 2, 92.48%:7.52%) in methanol (10 vol.)was heated to 60-65° C. with stirring for 1-2 h. Then the heating wasstopped and the solution was allowed to cool to 25-35° C. The mixturewas stirred for 24 h and then filtered. This afforded 8.0 g of(P)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2-oxo-2H-[1,4′-bipyridine]-2′-carboxylate(S)-1-(naphthalen-2-yl)ethan-1-aminium (Isomer 1 Salt A) with enhancedHPLC chiral purity (Isomer 1: Isomer 2, 95.26%:4.74%).

Step 5: Fourth purification of(P)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2-oxo-2H-[1,4′-bipyridine]-2′-carboxylate(S)-1-(naphthalen-2-yl)ethan-1-aminium (Isomer 1 Salt A). The wet solid,(P)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2-oxo-2H-[1,4′-bipyridine]-2′-carboxylate(S)-1-(naphthalen-2-yl)ethan-1-aminium (Isomer 1 Salt A), (Example 9,Step 4, 8.0 g, Isomer 1: Isomer 2, 95.26%:4.74%) in methanol (10 vol.)was heated to 60-65° C. with stirring for 1-2 h. Then the heating wasstopped and the solution was allowed to cool to 25-35° C. The mixturewas stirred for 24 h and then filtered. This afforded 6.0 g of(P)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2-oxo-2H-[1,4′-bipyridine]-2′-carboxylate(S)-1-(naphthalen-2-yl)ethan-1-aminium (Isomer 1 Salt A) with enhancedHPLC chiral purity (Isomer 1: Isomer 2, 98.29%:1.71%).

Step 6: Fifth purification of(P)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2-oxo-2H-[1,4′-bipyridine]-2′-carboxylate(S)-1-(naphthalen-2-yl)ethan-1-aminium (Isomer 1 Salt A). The wet solid,(P)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2-oxo-2H-[1,4′-bipyridine]-2′-carboxylate(S)-1-(naphthalen-2-yl)ethan-1-aminium (Isomer 1 Salt A), (Example 9,Step 5, 6.0 g, Isomer 1: Isomer 2, 98.29%:1.71) in methanol (10 vol.)was heated to 60-65° C. with stirring for 1-2 h. Then the heating wasstopped and the solution was allowed to cool to 25-35° C. The mixturewas stirred for 24 h and then filtered. This afforded 6.0 g of(P)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2-oxo-2H-[1,4′-bipyridine]-2′-carboxylate(S)-1-(naphthalen-2-yl)ethan-1-aminium (Isomer 1 Salt A) with enhancedHPLC chiral purity (Isomer 1: Isomer 2, 98.29%:4.74%).

Step 7: Synthesis of(P)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2-oxo-2H-[1,4′-bipyri-dine]-2′-carboxylicacid (CPD-07)

(P)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2-oxo-2H-[1,4′-bipyridine]-2′-carboxylate(S)-1-(naphthalen-2-yl)ethan-1-aminium (Isomer 1 Salt A) (Example 9,Step 6, 4.2 g, Isomer 1: Isomer 2, 98.29%:4.74%) was dissolved in water(42 mL, 10 vol.) and basified with 2N NaOH to pH ˜12. It was extractedthree times with EtOAc (42 mL, 10 vol.). The EtOAc extract contained(S)-1-(naphthalen-2-yl)ethan-1-amine. The aq. layer was acidified with2N HCl (pH 2) to precipitate the solid, The solid was filtered andwashed with n-heptane (2 vol.) to afford chiral,(P)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2-oxo-2H-[1,4′-bipyri-dine]-2′-carboxylicacid (2.3 g, Dry) HPLC chiral purity (Isomer I, Isomer 2, 99.86%:0.14%).

Example 10: Preparation of(P)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2-oxo-2H-[1,4′-bipyri-dine]-2′-carboxylicacid (CPD-07) via chiral separation with(1S,2R)-2-amino-1,2-diphenylethan-1-ol

Step 1: Synthesis of(P)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2-oxo-2H-[1,4′-bipyridine]-2′-carboxylate(1R,2S)-2-hydroxy-1,2-diphenylethan-1-aminium (Isomer 1 Salt B)

To a stirred suspension of3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2-oxo-2H-[1,4′-bipyri-dine]-2′-carboxylicacid (CPD-06, Example 8) (5 g, 1.0 eq.) in acetonitrile (100 mL, 20vol.) (250 mL RBF) was added 1.0 eq. of(1S,2R)-2-amino-1,2-diphenylethan-1-ol at 60-65° C. (Observation: Afteraddition of (1S,2R)-2-amino-1,2-diphenylethan-1-ol, a clear solution wasobserved). Stirring was continued at 60-65° C. for 1-2 h. The stirredsolution was allowed to cool to 25-35° C. for 24 h. The solid wasfiltered to afford 4 g of(P)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2-oxo-2H-[1,4′-bipyrid-ine]-2′-carboxylate(1R,2S)-2-hydroxy-1,2-diphenylethan-1-aminium (Isomer 1 Salt B) withenhanced HPLC chiral purity (Isomer 1: Isomer 2, 58.98%:41.02%). ¹H-NMR(400 MHz, DMSO-d₆): δ ppm 8.68 (s, 1H), 8.59 (d, 1H, J=2.4 Hz),8.05-8.14 (m, 1H), 7.45-7.57 (m, 2H), 7.81 (s, 1H), 7.08-7.25 (m, 11H),6.77 (s, 1H), 5.47 (d, 2H, J=1.6 Hz), 4.8-4.95 (m, 1H), 4.16-4.24 (m,1H), 2.08 (s, 3H), 2.06 (s, 3H), 1.91 (d, 3H, J=7.2 Hz); MS (ES) m/z422.28 (M+H).

Step 2: First purification of(P)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2-oxo-2H-[1,4′-bipyridine]-2′-carboxylate(1R,2S)-2-hydroxy-1,2-diphenylethan-1-aminium (Isomer 1 Salt B). The wetsolid,(P)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2-oxo-2H-[1,4′-bipyridine]-2′-carboxylate(1R,2S)-2-hydroxy-1,2-diphenylethan-1-aminium (Isomer 1 Salt B),(Example 10, Step 1, 4 g, Isomer 1: Isomer 2, 58.98%:41.02%) in methanol(10 vol.) was heated with stirring to 60-65° C. for 1-2 h to afford aclear solution. Then the heating was stopped, and the solution wasallowed to cool to 25-35° C. The mixture was stirred for 24 h andfiltered. This afforded 3.1 g(P)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2-oxo-2H-[1,4′-bipyridine]-2′-carboxylate(1R, 2S)-2-hydroxy-1,2-diphenylethan-1-aminium (Isomer 1 Salt B) withenhanced HPLC chiral purity (Isomer 1: Isomer 2, 75.72%:24.28%).

Step 3: Second purification of(P)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2-oxo-2H-[1,4′-bipyridine]-2′-carboxylate(1R,2S)-2-hydroxy-1,2-diphenylethan-1-aminium (Isomer 1 Salt B). The wetsolid,(P)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2-oxo-2H-[1,4′-bipyridine]-2′-carboxylate(1R,2S)-2-hydroxy-1,2-diphenylethan-1-aminium (Isomer 1 Salt B),(Example 10. Step 2, 3.1 g, Isomer 1: Isomer 2, 75.72%:24.28%) inmethanol (10 vol.) was heated with stirring to 60-65° C. for 1-2 h toafford a clear solution. Then the heating was stopped, and the solutionwas allowed to cool to 25-35° C. The mixture was stirred for 24 h andfiltered. This afforded 2.0 g of(P)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2-oxo-2H-[1,4′-bipyridine]-2′-carboxylate(1R,2S)-2-hydroxy-1,2-diphenylethan-1-aminium (Isomer 1 Salt B) withenhanced HPLC chiral purity (Isomer 1: Isomer 2, 81.27%:18.73%).

Step 4: Third purification of(P)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2-oxo-2H-[1,4′-bipyridine]-2′-carboxylate(1R,2S)-2-hydroxy-1,2-diphenylethan-1-aminium (Isomer 1 Salt B). The wetsolid,(P)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2-oxo-2H-[1,4′-bipyridine]-2′-carboxylate(1R,2S)-2-hydroxy-1,2-diphenylethan-1-aminium (Isomer 1 Salt B), (Step3, 2 g, Isomer 1: Isomer 2, 81.27%:18.73%) in methanol (10 vol.) washeated to 60-65° C. with stirring for 1-2 h. Then the heating wasstopped and the solution was allowed to cool to 25-35° C. The mixturewas stirred for 24 h and then filtered. This afforded 0.5 g of(P)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2-oxo-2H-[1,4′-bipyridine]-2′-carboxylate(1R,2S)-2-hydroxy-1,2-diphenylethan-1-aminium (Isomer 1 Salt B) withenhanced HPLC chiral purity (Isomer 1: Isomer 2, 99.19%:0.81%).

Step 5: Synthesis of(P)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2-oxo-2H-[1,4′-bipyri-dine]-2′-carboxylicacid (CPD-07)

(P)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2-oxo-2H-[1,4′-bipyridine]-2′-carboxylate(1R,2S)-2-hydroxy-1,2-diphenylethan-1-aminium (Isomer 1 Salt B) (Step 4,0.5 g, Isomer 1: Isomer 2, 99.19%:0.81%) was dissolved in water (5 mL,10 vol.) and basified with 2N NaOH to pH ˜12. It was extracted threetimes with EtOAc (5 mL, 10 vol.). The EtOAc extract contained(1S,2R)-2-amino-1,2-diphenylethan-1-ol. The aq. layer was acidified with2N HCl (pH 2) to precipitate the solid, The solid was filtered andwashed with n-heptane (2 vol.) to afford chiral,(P)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2-oxo-2H-[1,4′-bipyri-dine]-2′-carboxylicacid (0.25 g, Dry) HPLC chiral purity (Isomer 1: Isomer 2,99.19%:0.81%).

Example 11: Preparation of(M)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2-oxo-2H-[1,4′-bipyri-dine]-2′-carboxylicacid via chiral separation with (1R,2S)-2-amino-1,2-diphenylethan-1-ol(CPD-32)

Step 1: Synthesis of(M)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2-oxo-2H-[1,4′-bipyridine]-2′-carboxylate(1S,2R)-2-hydroxy-1,2-diphenylethan-1-aminium (Isomer 2 Salt C).

To a stirred suspension of3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2-oxo-2H-[1,4′-bipyri-dine]-2′-carboxylicacid (CPD-06, Example 8) (5.0 g, 1.0 eq.) in acetonitrile (100 mL, 20vol.) (250 mL RBF) was added 1.0 eq. of(1R,2S)-2-amino-1,2-diphenylethan-1-ol at 60-65° C. (Observation: Afteraddition of (1R,2S)-2-amino-1,2-diphenylethan-1-ol, a clear solution wasobserved). Then stirring was stirred at 60-65° C. for 1-2 h. The stirredsolution was allowed to cool to 25-35° C. for 24 h. The solid wasfiltered to afford 6.0 g of(M)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2-oxo-2H-[1,4′-bipyrid-ine]-2′-carboxylate(1S,2R)-2-hydroxy-1,2-diphenylethan-1-aminium (Isomer 2 Salt C) withenhanced HPLC chiral purity (Isomer 1: Isomer 2, 18.86%:81.14%). ¹H-NMR(400 MHz, DMSO-d6): δ ppm 8.68 (s. 1H), 8.59 (d, 1H, J=2.4 Hz),8.04-8.12 (m, 1H), 7.81 (s, 1H), 7.16-7.29 (m, 9H), 7.08-7.15 (m, 2H),6.77 (s, 1H), 5.47 (d, 2H, J=1.2 Hz), 4.90 (s, 1H), 4.21 (d, 1H), 2.03(s, 3H), 1.91 (s, 3H); MS (ES) m/z 422 (M+H).

Step 2: First purification of(M)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2-oxo-2H-[1,4′-bipyridine]-2′-carboxylate(1S,2R)-2-hydroxy-1,2-diphenylethan-1-aminium (Isomer 2 Salt C). The wetsolid,(M)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2-oxo-2H-[1,4′-bipyridine]-2′-carboxylate(1S,2R)-2-hydroxy-1,2-diphenylethan-1-aminium (Isomer 2 Salt C), (Step1, 6.0 g, Isomer 1: Isomer 2, 18.86%:81.14%) in methanol (10 vol.) washeated with stirring to 60-65° C. for 1-2 h to afford a clear solution.Then the heating was stopped and the solution was allowed to cool to25-35° C. The mixture was stirred for 24 h and filtered. This afforded4.0 g(M)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2-oxo-2H-[1,4′-bipyridine]-2′-carboxylate(1S,2R)-2-hydroxy-1,2-diphenylethan-1-aminium (Isomer 2 Salt C) withenhanced HPLC chiral purity (Isomer 1: Isomer 2, 15.487%:84.52%).

Step 3: Second purification of(M)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2-oxo-2H-[1,4′-bipyridine]-2′-carboxylate(1S,2R)-2-hydroxy-1,2-diphenylethan-1-aminium (Isomer 2 Salt C). The wetsolid,(M)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2-oxo-2H-[1,4′-bipyridine]-2′-carboxylate(1S,2R)-2-hydroxy-1,2-diphenylethan-1-aminium (Isomer 2 Salt C), (Step2, 4.0 g, Isomer 1: Isomer 2, 15.487%:84.52%) in methanol (10 vol.) washeated with stirring to 60-65° C. for 1-2 h to afford a clear solution.Then the heating was stopped and the solution was allowed to cool to25-35° C. The mixture was stirred for 24 h and filtered. This afforded2.0 g of(M)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2-oxo-2H-[1,4′-bipyridine]-2′-carboxylate(1S,2R)-2-hydroxy-1,2-diphenylethan-1-aminium (Isomer 2 Salt C) withenhanced HPLC chiral purity (Isomer 1: Isomer 2, 12.567%:87.44%).

Step 4: Third purification of(P)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2-oxo-2H-[1,4′-bipyridine]-2′-carboxylate(1S,2R)-2-hydroxy-1,2-diphenylethan-1-aminium (Isomer 2 Salt C). The wetsolid,(M)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2-oxo-2H-[1,4′-bipyridine]-2′-carboxylate(1S,2R)-2-hydroxy-1,2-diphenylethan-1-aminium (Isomer 2 Salt C), (Step3, 2.0 g, Isomer 1: Isomer 2, 12.567%:87.44) in methanol (10 vol.) washeated to 60-65° C. with stirring for 1-2 h. Then the heating wasstopped and the solution was allowed to cool to 25-35° C. The mixturewas stirred for 24 h and then filtered. This afforded 1.5 g of(M)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2-oxo-2H-[1,4′-bipyridine]-2′-carboxylate(1S,2R)-2-hydroxy-1,2-diphenylethan-1-aminium (Isomer 2 Salt C) withenhanced HPLC chiral purity (Isomer 1: Isomer 2, 0.137%:99.87%).

Step 5: Synthesis of(M)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2-oxo-2H-[1,4′-bipyri-dine]-2′-carboxylicacid

(M)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2-oxo-2H-[1,4′-bipyridine]-2′-carboxylate(1S,2R)-2-hydroxy-1,2-diphenylethan-1-aminium (Isomer 2 Salt C) (Step 4,1.5 g, Isomer 1: Isomer 2, 0.137%:99.87) was dissolved in water (5 mL,10 vol.) and basified with 2N NaOH to pH ˜12. It was extracted threetimes with EtOAc (5 mL, 10 vol.). The EtOAc extract contained(1R,2S)-2-amino-1,2-diphenylethan-1-ol. The aq. layer was acidified with2N HCl (pH 2) to precipitate the solid, The solid was filtered andwashed with n-heptane (2 vol.) to afford chiral,(M)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2-oxo-2H-[1,4′-bipyri-dine]-2′-carboxylicacid (0.25 g, Dry), HPLC chiral purity (Isomer 1: Isomer 2,0.137%:99.87%).

Example 12: Preparation of(P)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-2′-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one(Formula P-(I))

Step 1: Synthesis of(P)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-N-methoxy-N,5′,6-trimethyl-2-oxo-2H-[1,4′-bipyridine]-2′-carboxamide(CPD-08)

To a stirred solution of(P)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2-oxo-2H-[1,4′-bipyri-dine]-2′-carboxylicacid (CPD-07, Example 9, Step 7) (6.0 g, 1.0 eq, Isomer I, Isomer 2,99.86%:0.14%) in DMF (8 vol.) was addedN-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC•HCl(1.0 eq.)) at 0-5° C., and it was stirred for 5-10 min. TEA (1.0 eq.)was added at 0-5° C., and the mixture was stirred for 10-20 min. Then N,O-dimethyl hydroxylamine hydrochloride (1.5 eq.) was added at 0-5° C.The mixture was stirred for 1-2 h, and the progress of the reaction wasmonitored by TLC. After completion of the reaction, the reaction wasallowed to cool to 25-35° C. Ice-cold water (20.0 vol.) was added andstirring as continued for 30-45 min. The mixture was then extracted withEtOAc (3×10 vol.). The combined EtOAc layers were washed with ice-coldwater (10 vol.) and dried over anhydrous sodium sulphate. Afterfiltration, the EtOAc distilled-off completely and MTBE (2 vol.) wasadded, and it was stirred for 1-2 h. The solid was filtered and dried atbelow 45° C. to afford 5.0 g (yield: 75%) of(P)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-N-methoxy-N,5′,6-trimethyl-2-oxo-2H-[1,4′-bipyridine]-2′-carboxamidewith HPLC purity 99.0% along with HPLC Chiral purity (Isomer 1: Isomer2, 99.56%:0.44%). ¹H-NMR (400 MHz, DMSO-d6): δ ppm 8.70 (s, 1H), 8.59(d, 1H, J=2.4 Hz), 8.04-8.12 (m, 1H), 7.63 (s, 1H), 6.79 (s, 1H), 5.47(d, 2H, J=1.6 Hz), 3.67 (s, 3H), 3.29 (s, 3H), 2.04 (s, 3H), 1.93 (s,3H); MS (ES) m/z 465.31 (M+H).

Step 2: Synthesis of(P)-2′-Acetyl-3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one(CPD-09)

To a stirred solution of(P)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-N-methoxy-N,5′,6-trimethyl-2-oxo-2H-[1,4′-bipyridine]-2′-carboxamide(CPD-08, Example 12, Step 1) (5.0 g, Isomer 1: Isomer 2 (99.56%:0.44%)in dry THF (42 vol.) was slowly added MeMgBr (9.5 eq.; 2M solution inTHF) at 0-10° C. Then the reaction mass temperature was raised to 0-5°C. and maintained for 1 h. The reaction mass was quenched with 15% aq.ammonium chloride solution (10 vol.) and extracted with EtOAc (2×10vol.). The combined EtOAc layers were distilled-off completely to afforda crude solid. The solid was dissolved in dichloromethane (DCM (1 vol.))and then precipitated by adding hexanes (9 vol.) The solid was filteredto afford 3.0 g (yield: 66%) of(P)-2′-Acetyl-3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-onewith HPLC purity 98.80% and HPLC chiral purity (Isomer 1: Isomer 2,99.86%:0.14%). ¹H-NMR (400 MHz, DMSO-d6): δ ppm 8.83 (s, 1H), 8.59 (d,1H, J=2.4 Hz), 8.05-8.14 (m, 1H), 7.89 (s, 1H), 6.79 (s, 1H), 5.47 (d,2H, J=1.6 Hz), 2.66 (s, 3H), 2.09 (s, 3H), 1.91 (s, 3H); MS (ES) m/z420.08 (M+H).

Step 3: Synthesis of(P)-(E)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-2′-(3-(dimethyl-amino)acryloyl)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one(CPD-10)

To a stirred solution of(P)-2′-Acetyl-3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one(CPD-09, Example 12, Step 2) (2.0 g, 1.0 eq., Isomer 1: Isomer 2,99.86%:0.14%), was added N,N-dimethyl-formamide dimethyl acetal (DMF-DMA(8.0 eq.)) and DMF (1.0 vol.) at 25-35° C. The reaction mass was slowlyheated to 50-55° C. and maintained for at that temperature for 24 h.Progress of the reaction was monitored by TLC. After completion ofreaction, heating was stopped and the mixture was cooled to 25-35° C.Then dichloromethane (DCM) (10.0 vol.), and water (10.0 vol.) wereadded. The mixture was stirred for 10-15 min, and the phases wereseparated. The aqueous layer was extracted with DCM (2×10 vol.). Thecombined DCM layers were washed with ice cold water (2×10 vol.) and weredried with anhydrous sodium sulphate. The DCM layer was concentrated atbelow 35° C. to afford a crude solid. EtOAc (2.0 vol.) was added and themixture was stirred for 1-2 h at 25-35° C. The solid was filtered toafford 1.8 g (yield: 79.6%) of(P)-(E)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-2′-(3-(dimethyl-amino)acryloyl)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-onewith HPLC 97.05%, and HPLC chiral purity (Isomer 1: Isomer 2 (99.96%0.04%). ¹H-NMR (400 MHz, DMSO-d6): δ ppm 8.71 (s, 1H), 8.60 (d, 1H,J=2.4 Hz), 8.04-8.12 (m, 1H), 7.80-7.86 (m, 2H), 6.78 (s, 1H), 6.37 (d,1H, J=12.8 Hz), 5.47 (d, 2H, J=1.6 Hz), 3.19 (s, 3H), 2.94 (s, 3H), 2.05(s, 3H), 1.91 (s, 3H); MS (ES) m/z 475.36 (M+H).

Step 4: Synthesis of(P)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-2′-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one(Formula P-(I))

To a stirred solution of(P)-(E)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-2′-(3-(dimethyl-amino)acryloyl)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one(CPD-10, Example 12, Step 3) (5.4 g, 1.0 eq., Isomer 1: Isomer 2,99.96%:0.04%) in DMF (6.0 vol.) was added K₂CO₃ (2.5 eq.). Afterstirring for 5-10 min at 25-35° C., 2-hydroxy-2-methylpropionamidine HCl(INT-02) (3.0 eq.) at 25-35° C. was added. The reaction mass was slowlywarmed to 45-50° C. and was stirred at that temperature for 7 h.Progress of the reaction was monitored by TLC/IPC HPLC. After thereaction was completed, it was cooled to 10-15° C., diluted with water(20 vol.), and stirred for 1-2 h at 10-15° C. The solid was filtered anddried to afford 5.0 g of crude(P)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-2′-(2-(2-hydroxy-propan-2-yl)pyrimidin-4-yl)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one,HPLC chiral purity (Isomer 1: Isomer 2) (95% 5%).

Step 5: Purification of(P)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-2′-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one(Formula P-(I))

Crude(P)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-2′-(2-(2-hydroxy-propan-2-yl)-pyrim-idin-4-yl)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one(Formula P-(I), Example 12, Step 4) (5.0 g, 1.0 eq., Isomer 1: Isomer 2(95%:5%) in IPA (19.0 vol.) was stirred for 1 h at 72-75° C. Seedmaterial (Formula P-(I), Example 12, Step 4) (0.25 g, 0.05 w/w times,Seed Crystal's Assay is 98.4%) was then added at 72-75° C. Heating wasstopped and the mixture was allowed to cool to 25-35° C. After stirringfor 24 h the solid was filtered. The solid was washed with IPA (2.0vol.), and it was dried at below 40° C. to afford 4.4 g (yield: 75%) of(P)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-2′-(2-(2-hydroxypropan-2-yl)-pyrimidin-4-yl)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-onewith HPLC purity 99.52% and HPLC chiral purity (Isomer 1: Isomer 2,99.65%:0.35%). ¹H-NMR (400 MHz, DMSO-d₆): δ ppm 8.97 (d, 1H, J=5.2 Hz),8.86 (s, 1H), 8.69 (s, 1H), 8.61 (d, 1H, J=2.4 Hz), 8.24 (d, 1H, J=5.2Hz), 8.06-8.14 (m, 1H), 6.84 (s, 1H), 5.49 (d, 2H, J=1.2 Hz), 5.25 (s,1H), 2.10 (s, 3H), 1.98 (s, 3H), 1.04 (s, 3H), 1.03 (s, 3H); MS (ES) m/z514.37 (M+H).

Example 13: Preparation of3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-2′-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one (CPD-20) Via Sonogashira Coupling

Step 1: Synthesis of Preparation of4-((3,5-difluoropyridin-2-yl)methoxy)-2′-(3-hydroxyprop-1-yn-1-yl)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one(CPD-21)

To a pre-cleaned RBF was added water (5 vol, 200 mL) and 1,4-Dioxane (5vol, 200 mL). The solvent was then degassed with argon for 10 min.2′-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one(CPD-03, Example 5) (40.0 g, 106 mmol, 1 eq.), TPP (5.55 g, 21.2 mmol,0.2 eq.), TEA (73.8 mL, 530.0 mmol, 5 eq.), CuI (1.0 g, 5.3 mmol, 0.05eq.), and 10% Pd/C (11.29 g, 5.3 mmol, 0.05 eq.) were then added to theRBF. The mixture was degassed with argon for 10 min, and propargylalcohol (24.7 mL, 424.4 mmol, 4 eq.) was added to the reaction mixture.The mixture was stirred for 10 min at room temperature. The reactionmixture was then heated to 90° C. for 62 h and monitored by LC-MS. Aftercompletion, the reaction mixture was cooled to RT and filtered andwashed with EtOAc. The filtrate was extracted with EtOAc and was washedwith brine solution. The organic layer was dried over Na₂SO₄ and it wasconcentrated under reduced pressure to obtain crude4-((3,5-difluoropyridin-2-yl)methoxy)-2′-(3-hydroxyprop-1-yn-1-yl)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one(CPD-21). Crude compound (CPD-21) was purified by column chromatographyover silica gel (230-400 mesh), eluted with 2-4% MeOH in DCM to obtaindesired4-((3,5-difluoropyridin-2-yl)methoxy)-2′-(3-hydroxyprop-1-yn-1-yl)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one(CPD-21) as yellow solid (18.5 g, 44%) with HPLC purity 93%. ¹H-NMR (300MHz, CDCl₃) δ ppm: 8.59 (s, 1H), 8.41 (d, J=2.1 Hz, 1H), 7.29 (s, 1H),7.22 (s, 1H), 6.03 (d, J=2.4 Hz, 1H), 5.96 (m, 1H), 5.19 (d, J=1.8 Hz,2H), 4.50 (d, J=6.0 Hz, 2H), 2.13 (s, 3H), and 1.85 (s, 3H). MS(ES),m/z=398.79 (M+H).

Step 2: Synthesis of Preparation of3-(4-(4-((3,5-difluoropyridin-2-yl)methoxy)-6-methyl-2-oxopyridin-1(2H)-yl)-5-methylpyridin-2-yl)propiolaldehyde(CPD-22)

A stirred solution of4-((3,5-difluoropyridin-2-yl)methoxy)-2′-(3-hydroxyprop-1-yn-1-yl)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one(CPD-21, Example 13, Step 1) (18.0 g, 45.3 mmol, 1 eq.) in DCM (360 mL)under nitrogen atmosphere was cooled (ice-bath). Dess-Martin periodinane(9.0 g, 68.0 mmol, and 1.5 eq.) was added portion wise at 0° C. Theresulting reaction mixture was allowed to stir at room temperature for 3h. Progress of the reaction was monitored by TLC. After completion, thereaction mixture was cooled to 0° C. and it was treated with 10% aq.sodium thiosulfate, then extracted with DCM (180 mL×3), The organiclayer was washed with water, followed by brine, concentrated underreduced pressure to obtain3-(4-(4-((3,5-difluoropyridin-2-yl)methoxy)-6-methyl-2-oxopyridin-1(2H)-yl)-5-methylpyridin-2-yl)propiolaldehyde(CPD-22) as yellow liquid (16 g, 83%). The crude compound was used fornext step without further purification.

Step 3: Synthesis of4-((3,5-difluoropyridin-2-yl)methoxy)-1-(2-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-5-methylpyridin-4-yl)-6-methylpyridin-2(1H)-one(CPD-23)

To a stirred solution of3-(4-(4-((3,5-difluoropyridin-2-yl)methoxy)-6-methyl-2-oxopyridin-1(2H)-yl)-5-methylpyridin-2-yl)propiolaldehyde(CPD-22, Example 13, Step 2) (3.0 g, 7.59 mmol, 1 eq) in ACN (30 mL)were added Na₂CO₃ (2.3 g, 22.78 mmol, 3 eq) and2-hydroxy-2-methylpropionamidine HCl (INT-02, 1.17 g, 11.39 mmol, 1.5eq) at rt. The reaction mixture was heated at 80° C.-85° C. for 2 h. Thereaction progress was monitored by TLC and LC-MS. After completion, thereaction mixture was cooled to room temperature. It was filtered andwashed with ACN. The filtrate was concentrated under reduced pressure toobtain4-((3,5-difluoropyridin-2-yl)methoxy)-1-(2-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-5-methylpyridin-4-yl)-6-methylpyridin-2(1H)-one(CPD-23) as a brown solid (3.6 g, 97%) with HPLC purity of 66%. Thecrude compound was used for next step without further purification.¹H-NMR (300 MHz, CDCl₃) δ ppm: 8.86 (d, J=5.1 Hz, 1H), 8.74 (s, 1H),8.42-8.41 (m, 1H), 8.27-8.25 (m, 2H), 7.30-7.33 (m, 1H), 6.08 (d, J=2.1Hz, 1H), 6.03 (d, J=0.9 Hz, 1H), 5.22 (s, 2H), 5.19 (br-s, 1H), 2.22 (s,3H), 1.90 (s, 3H), 1.64 (s, 3H), and 1.63 (s, 3H). MS (ES) m/z=480.89(M+H).

Step 4: Synthesis of3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-2′-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one(CPD-20)

A mixture of4-((3,5-difluoropyridin-2-yl)methoxy)-1-(2-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-5-methyl-pyridin-4-yl)-6-methylpyridin-2(1H)-one(CPD-23, Example 13, Step 3) (3.6 g, 7.515 mmol), N-chlorosuccinimide(1.19 g, 9.018 mmol, 1.2 eq) in DCM (108 mL) containing dichloroaceticacid (0.387 g, 3.006 mmol, 0.4 eq.) was heated at 60° C. under nitrogenfor 2 h. The reaction mixture was cooled to room temperature and dilutedwith DCM. It was then basified with aq. NaHCO₃ solution. The layers wereseparated. The aqueous layer was extracted with DCM. The combinedextracts were washed with brine, dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The crude compound was purified bycolumn chromatography over silica-gel (230-400 mesh), using 2-4% MeOH aseluent to obtain3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-2′-(2-(2-hydroxy-propan-2-yl)pyrimidin-4-yl)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one (CPD-20) as yellow solid (1.2 g,31% yield) with HPLC purity 92%, ¹H-NMR (400 MHz, DMSO-d6) δ ppm: 8.97(d, J=5.2 Hz, 1H), 8.86 (s, 1H), 8.69 (s, 1H), 8.61 (d, J=2.0 Hz, 1H),8.24 (d, J=5.4 Hz, 1H), 8.13-8.07 (m, 1H), 6.84 (s, 14H), 5.49 (d, J=1.2Hz, 2H), 5.25 (br-s, 1H), 2.17 (s, 3H), 1.98 (s, 3H), 1.54 (s, 3H), 1.53(s, 3H). MS (ES) m/z 514.89 (M+H).

Example 14: Preparation of2′-acetyl-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one(CPD-17) Via Reductive Cyanation

Step 1: Synthesis of4-((3,5-Difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2-oxo-2H-[1,4′-bipyridine]-2′-carbonitrile(CPD-24)

To a solution of2′-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one(CPD-03, Example 5) (1 g, 2.65 mmol), zinc cyanide (186.2 mg, 1.59 mmol,0.6 eq), Pd₂(dba)₃ (48.54 mmol, 0.05 mmol, 0.02 eq), zinc powder (6.94mg, 0.11 mmol, 0.04 eq) and diphenylphopshinoferrocene (176.4 mg, 0.32mmol, 0.12 eq.) were sequentially added, and the reaction mass wasdegassed with nitrogen for 30 minutes. The reaction mixture was heatedto 120° C. for 18h. The reaction was monitored by LCMS which showed ˜59%desired mass and ˜5-% of4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2-oxo-2H-[1,4′-bipyridine]-2′-carboxylicacid. The reaction mixture was cooled to RT, diluted with ethyl acetate,and washed with water. The organic layer was dried over anhydrous sodiumsulfate, and it was concentrated under reduced pressure. The crudeproduct was purified by column chromatography over silica-gel using 1:1ethyl acetate-hexanes mixture to afford the desired product4-((3,5-Difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2-oxo-2H-[1,4′-bipyridine]-2′-carbonitrile(CPD-24) (400 mg, 41%) with purity of 75%. ¹H-NMR (300 MHz, DMSO-d6) δppm: 8.84 (brs, 1H), 8.59 (d, 1H, J=2.1 Hz), 8.12 (s, 1H), 8.11-8.04 (m,1H), 6.12 (d, 1H, J=1.5 Hz), 6.05 (d, 1H, 2.4 Hz), 5.25 (2, 2H), 2.10(s, 3H), 1.84 (s, 1H). MS (ES) m/z 369.20 (M+H).

Step 2: Synthesis of2′-acetyl-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one(CPD-17)

To a solution4-((3,5-Difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2-oxo-2H-[1,4′-bipyridine]-2′-carbonitrile(CPD-24, Example 14, Step 1) (50 mg, 0.136 mmol) in THF (5 mL) was added3M methylmagnesium iodide in THF (0.0.2 mL, 0.6 mmol, 4.4 eq) at RT. Thereaction mixture was stirred at room temperature for 12h. It wasquenched with saturated ammonium chloride solution (0.5 mL). The organiclayer was separated and concentrated. The crude2′-acetyl-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one(CPD-17) was isolated and analyzed by MS (ES) m/z 386.29 (M+H).

Example 15: Preparation of Methyl 4-((3,5-difluoropyridin-2-yl)methoxy)-5′, 6-dimethyl-2-oxo-2H-[1,4′-bipyridine]-2′-carboxylate (CPD-04) Via Brominated Intermediates

Step 1: Synthesis of2′-bromo-4-hydroxy-5′,6-dimethyl-2H-[1,4′-bipyridine]-2-one (CPD-25)

A stirred mixture of2′-chloro-4-hydroxy-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one (CPD-02,Example 3) (10.0 g, 40 mmol, 1 eq.) 33% HBr in AcOH (150 mL, 15 vol.)and NaBr (4.115 g, 40 mmol, 1 eq.) was heated to 90° C. for 36 h. Aftercompletion, the reaction mixture was cooled to room temperature. Thesolid was filtered and dried to obtain2′-bromo-4-hydroxy-5′,6-dimethyl-2H-[1,4′-bipyridine]-2-one (CPD-25) aslight grey color solid (14 g, crude) with a crude HPLC purity of 88%.¹H-NMR (400 MHz), DMSO-d₆ δ: 10.78 (brs, 1H), 8.48 (s, 1H), 7.69 (s,1H), 6.03-6.02 (m, 1H), 5.65 (d, J=2.4 Hz, 1H), 1.96 (s, 3H), 1.84 (s,3H). MS (ES) m/z 296 (M+H).

Step 2: Synthesis of2′-bromo-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one(CPD-26)

To a stirred suspension of2′-bromo-4-hydroxy-5′,6-dimethyl-2H-[1,4′-bipyridine]-2-one (CPD-25,Example 15, Step 1) (14 g, 37.4 mmol, 1 eq.) in DMF (56 mL, 4 vol.) wasadded K₂CO₃ (12.9 g, 93.5 mmol, 2.5 eq.) followed by a solution of2-(chloromethyl)-3,5-difluoro-pyridine (INT-01, Example 4) (6.73 g, 41.1mmol, 1.1 eq.) in DMF (14 mL, 1 vol). The resulting reaction mixture wasstirred at room temperature for 32 h (reaction mixture became lightgreenish color after 10 min). Progress of the reaction was monitored byTLC. After completion, the reaction mixture was quenched with ice coldwater (140 mL) and extracted with EtOAc (140 ml×2). The combined organiclayer was washed with water (70 mL), followed by brine (70 mL). It wasconcentrated under reduced pressure to obtain2′-bromo-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one(CPD-26) as dark liquid (12.5 g, 79%) with HPLC purity of 81%. ¹H-NMR(400 MHz, DMSO-d₆) δ ppm: 8.59 (d, J=2.4 Hz, 1H), 8.47 (s, 1H),8.09-8.04 (m, 1H), 7.72 (s, 1H), 6.13-6.12 (d, 1H, J=2.4 Hz), 6.03 (d,J=2.4 Hz, 1H), 5.24 (d, J=1.6 Hz, 2H), 1.96 (s, 3H), 1.85 (s, 3H). MS(ES) m/z 423.91 (M+2H).

Step 3: Synthesis of Methyl4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2-oxo-2H-[1,4′-bipyridine]-2′-carboxylate(CPD-04)

In a pre-cleaned 600 mL autoclave,2′-bromo-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one(CPD-26, Example 15, Step 2) (4 g, 9.5 mmol) was taken followed bymethanol (64 mL, 16 vol.) and DMF (64 mL, 16 vol.) under argonatmosphere. The reaction mixture was de-gassed with argon for 15minutes. Triethylamine (2.61 mL, 19.0 mmol, 2 eq.) was added and themixture was degassed with argon for another 15 min. Pd(dppf)Cl₂•DCMcomplex (0.775 g, 0.95 mmol, 0.1 eq) was added, and the autoclave wasclosed. Carbon monoxide gas was charged at 100 psi and the pressure wasreleased. It was again pressurized with CO gas at 200 psi, and thereaction mass was stirred and heated at 100° C. for 16 h. The reactionwas monitored by TLC and LCMS. The reaction mixture was distilled toremove volatiles. It was filtered through a celite pad, and the pad waswashed with EtOAc (40 mL×2). The filtrate was stirred with ice coldwater (640 mL) and was extracted with EA (3×500 mL). The combinedextract was washed with water, dried over Na₂SO₄, and concentrated underreduced pressure to obtain crude CPD-04. The crude compound wassuspended in MTBE, stirred for 1 h, and filtered to obtain Methyl4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2-oxo-2H-[1,4′-bipyridine]-2′-carboxylate(CPD-04) as a brown solid (3.1 g, 81%) with HPLC purity of 77%. ¹H-NMR(400 MHz, DMSO-d₆) δ ppm: 8.79 (s, 1H), 8.59 (d, J=2.0 Hz, 1H),8.10-8.05 (m, 1H), 7.92 (s, 1H), 6.14-6.13 (m, 1H), 6.04 (d, J=2.4 Hz,1H), 5.25 (d, J=2.0 Hz, 2H), 3.89 (s, 3H), 2.09 (s, 3H), 1.81 (s, 3H).MS (ES) m/z 402.09 (M+H).

Example 16: Preparation of4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2-oxo-2H-[1,4′-bipyridine]-2′-carboxylicacid (CPD-11) from Methyl4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2-oxo-2H-[1,4′-bipyridine]-2′-carboxylate(CPD-04)

To a stirred suspension of Methyl4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2-oxo-2H-[1,4′-bipyridine]-2′-carboxylate(CPD-04, Example 6) in THF (5 vol.) was added a solution of LiOH·H₂O(3.0 eq.) in water (5 vol.) at 25-35° C. and continued stirring thereaction mass for 2-4 h. The progress of the reaction was monitored byTLC. Then aq. layer was washed with EtOAc (5 vol.) and the pH of aq.layer was adjusted to 2-3 using 4M HCl solution. The aqueous layer wasextracted with DCM (3×10 vol.). The combined DCM layer was dried oversodium sulphate and concentrated under reduced pressure at below 40° C.to afford4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2-oxo-2H-[1,4′-bipyridine]-2′-carboxylicacid as a light brown colored solid with HPLC Purity 98.7% and havingthe ratio of atropisomers 51.5%: 48.5%. ¹H-NMR (400 MHz, DMSO-d6) δ ppm:13.26 (br s, 1H) 8.77 (s, 1H), 8.59 (s, 1H), 8.07-8.15 (m, 1H), 7.88 (s,1H), 6.13 (s, 1H), 6.04 (d, J=2.4 Hz, 1H), 5.25 (d, J=1.6 Hz, 2H), 2.08(s, 3H), 1.82 (s, 3H). MS (ES) m/z 388.17 (M+H).

Example 17: Preparation of(P)-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2-oxo-2H-[1,4′-bipyri-dine]-2′-carboxylicAcid (CPD-12)

The racemic mixture of atropisomers4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2-oxo-2H-[1,4′-bipyridine]-2′-carboxylicacid (Example 16) were separated using super critical fluidchromatography (SFC) (see Table 3). Fraction-1((P)-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2-oxo-2H-[1,4′-bipyridine]-2′-carboxylicacid) after concentration afforded chiral purity Isomer 1: Isomer 2(97.7%: 2.3%). ¹H-NMR (400 MHz, DMSO-d6) δ ppm: 13.26 (br s, 1H) 8.75(s, 1H), 8.59 (d, J=2.8 Hz, 1H), 8.12-8.05 (m, 1H), 7.91 (s, 1H), 6.13(d, J=2.0 Hz, 1H), 6.03 (d, J=2.0 Hz, 1H), 5.24 (d, J=1.6 Hz, 2H), 2.08(s, 3H), 1.82 (s, 3H). MS (ES) m/z 388.17 (M+H), and the separatedFraction-2((M)-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2-oxo-2H-[1,4′-bipyridine]-2′-carboxylicacid) HPLC chiral purity is Isomer 1:Isomer 2 (2.7%:97.3%) respectively.¹H-NMR (400 MHz, DMSO-d6) δ ppm: 13.24 (br s, 1H) 8.76 (s, 1H), 8.59 (d,J=2.0 Hz, 1H), 8.13-8.05 (m, 1H), 7.91 (s, 1H), 6.13 (d, J=1.6 Hz, 1H),6.03 (d, J=2.8 Hz, 1H), 5.24 (d, J=1.8 Hz, 2H), 2.08 (s, 3H), 1.82 (s,3H). MS (ES) m/z 388.17 (M+H).

TABLE 3 SFC Conditions Mobile Phase 0.1% TFA in Methanol. ColumnChiral pack IG 250 mm* 4.6 m *5.0 μm Flow Rate 1.0 mL/minInjection Volume 10.0 μL Run Time 25.0 minutes Column Temperature 35° C.Wavelength 215 nm Diluent Methanol. Sample Concentration0.7 mg/mL for all stages

Example 18: Alternative Preparation of(P)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2-oxo-2H-[1,4′-bipyri-dine]-2′-carboxylicacid (CPD-07) via chiral separation with(S)-1-(naphthalen-2-yl)ethan-1-amine

Step 1: Synthesis of(P)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2-oxo-2H-[1,4′-bipyridine]-2′-carboxylate(S)-1-(naphthalen-2-yl)ethan-1-aminium (Isomer 1 Salt A)

To the filtered mother liquors (FmL's) of Example 9, Step 3, (1 g,Isomer 1: Isomer 2, (8: 91)) was added toluene (10 vol.) at 25-35° C.Then the reaction mass temperature was raised to 110-115° C., and it wasstirred at 110-115° C. for 48 h. An aliquot of the solid was removedfrom the heterogeneous mixture, and it was filtered. The solid wasanalyzed by chiral HPLC to confirm the configuration of the salt as thedesired isomer. The reaction mass was filtered and dried under vacuum toafford chiral amine salt, Isomer 1,(P)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2-oxo-2H-[1,4′-bipyridine]-2′-carboxylate(S)-1-(naphthalen-2-yl)ethan-1-aminium (Isomer 1 Salt A) with chiralpurity of Isomer 1: Isomer 2 (96.1%:3.1%) and HPLC purity of 98.4%.

Step 2 Synthesis of(P)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2-oxo-2H-[1,4′-bipyridine]-2′-carboxylicacid (CPD-07). The resulting chiral amine salt of Example 18, Step 1((P)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2-oxo-2H-[1,4′-bipyridine]-2′-carboxylate(S)-1-(naphthalen-2-yl)ethan-1-aminium (Isomer 1 Salt A) (0.6 g, Isomer1:Isomer 2 (96.1%:3.1%)) was dissolved in water (6.0 mL) and basifiedwith 2N NaOH to pH ˜12 and extracted with MTBE. The resulting MTBE layercontaining the amine was discarded. The aqueous layer pH was adjusted upto pH=2 with 2N HCl. Solid precipitation was observed. The precipitatedsolid was washed and dried under vacuum to afford 0.4 g of(P)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2-oxo-2H-[1,4′-bipyridine]-2′-carboxylicacid with HPLC chiral purity Isomer 1:Isomer 2 (95.22%:4.78%) and 98.16%of HPLC purity. ¹H-NMR (400 MHz, DMSO-d6): δ ppm 13.35 (br s, 1H), 8.80(s, 1H), 8.60 (d, 1H, J=2.4 Hz), 8.07-8.12 (m, 1H), 7.97 (s, 1H), 6.80(s, 1H), 5.47 (d, 2H, J=1.6 Hz), 2.08 (s, 3H), 1.93 (s, 3H). MS (ES) m/z422.12 (M+H).

Example 19: Preparation of2′-acetyl-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one(CPD-17) from CPD-03

Step 1: Synthesis of2′-(1-butoxyvinyl)-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one(CPD-27). To a stirred suspension of2′-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one(CPD-03, Example 5) (3.0 g, 7.94 mmol) in iPr₂NEt (2.8 mL, 16.08 mmol),was added ethylene glycol (15 mL) and butyl vinyl ether (5.1 mL). Themixture was warmed in an oil bath to 35° C. with stirring while bubblingN₂ through mixture. Solid Pd(OAc)₂ (0.10 g, 0.397 mmol, 5 mol %) and1,1′-Ferrocenediyl-bis(diphenylphosphine) (dppf) (0.44 g, 0.795 mmol, 10mol %) were charged to the mixture sequentially, and the bath was heatedto 110° C. After 3 h at 110° C. and 3 h more at 120° C., reactionwas >95% complete by IPC-LCMS. The mixture was cooled and partitionedbetween water and EtOAc. The aq. phase was extracted again with EtOAc.The combined organic phase was washed with water and filtered through apad of silica gel, eluting with EtOAc until all enol ether product wascollected. The fractions containing product were evaporated to afford2′-(1-butoxyvinyl)-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one(CPD-27) as a tan solid, 0.310 g (yield: 10%), HPLC purity 80%. ¹H-NMR(400 MHz, CDCl₃) δ ppm: 8.56 (s, 1H), 8.40 (s, 1H), 7.41 (s, 1H),7.24-7.32 (m, 2H), 6.04 (s, 1H), 5.96 (s, 1H), 5.44 (s, 1H), 5.19 (s,2H), 4.36 3.84-3.91 (m, 2H), 2.11 (s, 3H), 1.85 (s, 3H), 1.72-1.80 (m,2H), 1.42-1.51 (m, 2H), 0.96 (t, J=7.3 Hz, 3H); MS (ES) m/z 386.29(M+H).

Step 2: Synthesis of2′-acetyl-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one(CPD-17).2′-(1-butoxyvinyl)-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one(CPD-27 Example 19, Step 1) (0.250 g, 0.663 mmol) was treated with 8 mLof 3 N HCl at RT. After stirring vigorously for 30 min, the reaction wascomplete by IPC-HPLC. The mixture was transferred to a separatory funnelwith EtOAc and water. A small amount of saturated aq. NaCl was added,and the mixture mixed well and allowed to separate. The phases wereseparated and the aq. extracted again w/EtOAc after neutralizing(K₃PO₄/aq. KOH). The combined organic extract was washed with water, andboth aq. phases were back-extracted again with EtOAc. All of the organicphases were combined and vacuum filtered through a pad of silica gel.The filtrate was evaporated, and the residue chromatographed over silicagel with 0-30% 2-Methytetrahydrofuran in EtOAc. Pooled and evaporatedall fractions containing desired product. The residue was dried furtheron a high vacuum line to get a tan foam of2′-acetyl-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one(CPD-17), 0.152 g (70% yield). ¹H-NMR (400 MHz, DMSO-d6) δ ppm: 8.68 (s,1H), 8.41 (s, 1H), 7.81 (s, 1H), 7.30-7.36 (m, 1H), 6.06 (s, 1H), 5.96(s, 1H), 5.18 (s, 2H), 2.73 (s, 3H), 2.20 (s, 3H), 1.83 (s, 3H); MS (ES)m/z 385.15 (M+H).

Example 20: Alternative Preparation of2′-acetyl-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one(CPD-17) from CPD-26

Step 1: Synthesis of2′-(1-butoxyvinyl)-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one(CPD-27). To a stirred suspension of2′-bromo-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one(CPD-26) (Example 15, Step 2, 5.0 g, 11.84 mmol), iPr₂NEt (4.1 mL, 23.68mmol), butyl vinyl ether (7.7 mL, 59.21 mmol), and ethylene glycol (25mL) under N₂ was warmed in an oil bath to 40° C. with stirring whilebubbling N₂ through mixture. Solid Pd(OAc)₂ (0.11 g, 0.474 mmol, 4 mol%) and dppf (0.53 g, 0.947 mmol, 8 mol %) were added sequentially, andthe oil bath was heated to 100° C. After a total of 15 h at 100° C.,IPC-HPLC was >98% desired product. The mixture was cooled to RT andtreated with 8 mL of 3 N HCl. After stirring vigorously for 30 min, thereaction was complete (HPLC). The mixture was transferred to aseparatory funnel with EtOAc and water. A small amount of saturated aq.NaCl was added, and the mixture mixed well and allowed to separate. Thephases were separated and the aq. extracted again w/EtOAc afterneutralizing (K₃PO₄/aq. KOH). The combined organic extract was washedwith water, and both aq. phases were back-extracted again with EtOAc.Combined organic layers vacuum filtered through a pad of silica gel. Thefiltrate was evaporated, and the residue chromatographed over silica gelwith 0-30% 2-methyltetrahydrofuran in EtOAc. Combined desired fractions,concentrated and dried under high vacuum to afford2′-(1-butoxyvinyl)-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one(CPD-27) as a tan foam, 2.35 g (yield: 52%). ¹H NMR (400 MHz, CDCl₃) δppm: 8.56 (s, 1H), 8.40 (s, 1H), 7.41 (s, 1H), 7.24-7.32 (m, 2H), 6.04(s, 1H), 5.96 (s, 1H), 5.44 (s, 1H), 5.19 (s, 2H), 4.36 3.84-3.91 (m,2H), 2.11 (s, 3H), 1.85 (s, 3H), 1.72-1.80 (m, 2H), 1.42-1.51 (m, 2H),0.96 (t, J=7.3 Hz, 3H); MS (ES) m/z 386.29 (M+H).

Step 2: Synthesis of2′-acetyl-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one(CPD-17). To a stirred suspension of2′-(1-butoxyvinyl)-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one(CPD-27) (Example 20, Step 1, 2.0 g, 5 mmol) was added2-methyltetrahydrofuran followed by 3N HCl to ˜pH 2. The resultingmixture was stirred vigorously at RT for 30 min, whereupon the reactionwas complete. The acid was neutralized with sat'd KHCO₃ (CO₂off-gassing), and the product was extracted into two portions of EtOAc.The combined organic phase was washed twice with water, then filteredthrough a pad of silica gel, eluting with EtOAc. Combined desiredfraction and concentrated, then further dried on a high vacuum line toafford2′-acetyl-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one(CPD-17) as a light yellow, free-flowing foam, 1.46 g (yield: 70%)¹H NMR(400 MHz, CDCl₃) δ ppm: 8.68 (s, 1H), 8.40 (s, 1H), 7.81 (s, 1H),7.30-7.36 (m, 1H), 6.03 (s, 1H), 5.97 (s, 1H), 5.19 (s, 2H), 2.72 (s,3H), 2.20 (s, 3H), 1.83 (s, 3H): MS (ES) m/z 386.29 (M+H).

Example 21: Alternative Preparation of2′-acetyl-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one(CDP-17) from CPD-26

To a stirred suspension of2′-bromo-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one(CPD-26) (Example 15, Step 2, 5.0 g, 11.84 mmol), was added iPr₂NEt (4.1mL, 23.68 mmol), hydroxyethyl vinyl ether (5.3 mL, 59.2 mmol), NMP (13mL), and water (13 mL) under N₂. The mixture was warmed with stirring to45° C. while bubbling N₂ through mixture. Solid Pd(OAc)₂ (0.08 g, 0.36mmol, 3 mol %) nd 1,3-bis(diphenylphosphino)propane (dppp) (0.29 g, 0.71mmol, 6 mol %) were added sequentially, and the oil bath was heated to95° C. for 24 h until the IPC-HPLC was 91.8% desired product. Themixture was cooled resulting in a clear, light brown solution. Themixture was diluted with 2-methyltetrahydrofuran and treated with 3 NHCl to ˜pH 2 and stirred vigorously at RT for 30 min, IPC-HPLC indicatedno starting material remained. The acid was neutralized with sat'd KHCO₃(CO₂ off-gassing), and the product was extracted into two portions ofEtOAc. The combined organic phase was washed twice with water, thenfiltered through a pad of silica gel, eluting with EtOAc. Combineddesired fractions, concentrated and dried on high vacuum to afford2′-acetyl-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one(CDP-17) as a light yellow, free-flowing foam, 3.8 g (yield: 70%). ¹HNMR (400 MHz, CDCl₃) δ ppm: 8.68 (s, 1H), 8.40 (s, 1H), 7.81 (s, 1H),7.30-7.36 (m, 1H), 6.03 (s, 1H), 5.97 (s, 1H), 5.19 (s, 2H), 2.72 (s,3H), 2.20 (s, 3H), 1.83 (s, 3H): MS (ES) m/z 386.26 (M+H).

Example 22: Alternative Preparation of2′-acetyl-3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one(CPD-18) from CPD-28

To a stirred suspension of2′,3-dichloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one(CPD-28) (Example 40, 1 g, 2.43 mmol, 1 eq) in 1,4-dioxane (7.5 ml, 7.5vol). Tributyl-(1-ethoxyvinyl)stannane (1.228 g, 3.640 mmol, 1.5 eq) wasadded at rt under argon atmosphere. Reaction mass was degassed withargon for 10 minutes. Copper iodide (23.13 mg, 0.121 mmol, 0.05 eq) andPd(dppf)Cl₂-DCM complex (79.47 mg, 0.0973 mmol, 0.04 eq) were addedunder argon atmosphere. Reaction mass was degassed with argon for 5minutes. The reaction mixture was heated in oil bath at 100-105° C. for16 h, IPC-LCMS was 86% complete. Reaction mixture was cooled to rt,diluted with 1,4-dioxane (5 ml), filtered through celite and washed with1,4-dioxane. The combined organic layer was concentrated to 50%, cooledto 0-5° C. 36% HCl (1 ml, 1 vol) was added slowly below 5° C. andreaction mass was stirred for 1 h. Reaction mass was solidified slowly,it was diluted with petroleum ether and filtered. The solid wassuspended in DCM (20 ml), cooled to 0-5° C. and basified with 20% NaOH(aq) solution. Separated the two layers and aqueous layer was againextracted with DCM (10 ml). The combined organic layer was dried overNa₂SO₄ and evaporated to afford crude compound. The crude compound waspurified by column chromatography using 100-200 mesh silica gel,combined desired fraction, concentrated and dried under high vacuum toafford2′-acetyl-3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one(CPD-18) as an off-white solid, 800 mg (yield: 78%). ¹H-NMR (400 MHz,DMSO-d6) δ ppm: 8.70 (s, 1H), 8.40 (d, 1H, J=2.4 Hz), 7.78 (s, 1H), 7.34(m, 1H), 6.37 (s, 1H), 5.41 (d, 2H, J=1.6 Hz), 2.73 (s, 3H), 2.18 (s,3H), 1.93 (s, 3H); MS (ES) m/z 420.14 (M+H).

Example 23: Alternative Preparation of2′-acetyl-3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one(CPD-18) from CPD-28

Step 1: Synthesis of2′-(1-butoxyvinyl)-3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one(CPD-29). To a stirred suspension of2′,3-dichloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one(CPD-28) (Example 40, 5.0 g, 12.13 mmol) was added iPr₂NEt (4.2 mL,24.26 mmol), butyl vinyl ether (1.9 mL, 14.56 mmol, 1.2 equiv), andethylene glycol (25 mL). The mixture was warmed in an oil bath to 35° C.with stirring while bubbling N₂ through mixture. Solid Pd(OAc)₂ (0.14 g,0.606 mmol, 5 mol %) and dppf (0.67 g, 1.21 mmol, 10 mol %) were chargedto the mixture sequentially, and the bath was heated to 115° C. for 9 hthe mixture was cooled to RT and partitioned between water and EtOAc.The aq. phase was extracted again with EtOAc, and the combined organicphase washed twice with water, filtered through a pad of silica gel,eluting with EtOAc. Combined desired fractions, concentrated and driedunder high vacuum to afford2′-(1-butoxyvinyl)-3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one(CPD-29) as a tan foam. No further purification was performed and thematerial was carried onto Step 2. ¹H-NMR (400 MHz, DMSO-d6) δ ppm: 8.55(s, 1H), 8.38 (s, 1H), 7.37 (s, 1H), 7.28-7.36 (m, 1H), 6.35 (s, 1H),5.44 (s, 1H), 5.38 (s, 2H), 4.36 (s, 1H), 3.84-3.91 (m, 2H), 2.07 (s,3H), 1.93 (s, 3H), 1.70-1.78 (m, 2H), 1.40-1.49 (m, 2H), 0.94 (t, J=7.3Hz, 3H); MS (ES) m/z 476.10 (M+H).

Step 2: Synthesis of2′-acetyl-3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one(CPD-18). The mixture from Step 1 containing2′-(1-butoxyvinyl)-3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one(CPD-29) (Step 1) at RT was treated with 8 mL of 3 N HCl. After stirringvigorously for 30 min, IPC-HPLC shows no starting material remaining.The mixture was partitioned between EtOAc and brine. The aqueous phasewas extracted again w/EtOAc after neutralizing (K₃PO₄/aq. KOH). Thecombined organic extract was washed with water, and both aq. phases wereback-extracted again with EtOAc. All of the organic phases were combinedand vacuum filtered through a pad of silica gel. The filtrate wasevaporated, and the residue chromatographed over silica gel with 0-30%2-methytetrahydrofuran in EtOAc. Combined desired fractions,concentrated and dried under high vacuum to afford2′-acetyl-3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one(CPD-18) as a light tan foam, 2.35 g (yield: 52%). ¹H-NMR (400 MHz,DMSO-d6) δ ppm: 8.70 (s, 1H), 8.40 (d, 1H, J=2.4 Hz), 7.78 (s, 1H), 7.34(m, 1H), 6.37 (s, 1H), 5.41 (d, 2H, J=1.6 Hz), 2.73 (s, 3H), 2.18 (s,3H), 1.93 (s, 3H); MS (ES) m/z 420.14 (M+H).

Example 24: Alternative Preparation of2′-acetyl-3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one(CPD-18) from CPD-30

Step 1: Synthesis of2′-(1-butoxyvinyl)-3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one(CPD-29). To a stirred suspension of2′-bromo-3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one(CPD-30) (Example 37, 7.0 g, 15.33 mmol) was added iPr₂NEt (5.3 mL,30.66 mmol), hydroxyethyl vinyl ether (56.9 mL, 76.64 mmol), NMP (18 mL)and water (18 mL). The mixture was warmed with stirring to 45° C. whilebubbling N₂ through mixture. Solid Pd(OAc)₂ (0.1 g, 0.46 mmol, 3 mol %)and 1,3-bis(diphenylphosphino)propane (dppp) (0.38 g, 0.92 mmol, 6 mol%) were added sequentially, and the oil bath was heated to 92° C.Heating at 92-94° C. was continued for 28 h, with the reaction progressbeing monitored by HPLC and TLC. Conversion was very slow initially, sosmall additional charges of Pd(OAc)₂ were added after about 3 and 21 hof heating. The reaction was terminated after 28 h of heating, havingnever been homogeneous. the mixture was cooled to RT and partitionedbetween water and EtOAc. The aqueous phase was extracted again withEtOAc, and the combined organic phase washed twice with water, filteredthrough a pad of silica gel, eluting with EtOAc. Combined desiredfractions, concentrated and dried under high vacuum to afford2′-(1-butoxyvinyl)-3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one(CPD-29) as a tan foam, 1.03 g (yield: 15%). No further purification wasperformed and the material was carried onto Step 2. ¹H-NMR (400 MHz,DMSO-d6) δ ppm: 8.55 (s, 1H), 8.38 (s, 1H), 7.37 (s, 1H), 7.28-7.36 (m,1H), 6.24 (s, 1H), 5.44 (s, 1H), 5.38 (s, 2H), 4.32 (s, 1H), 3.83-3.90(m, 2H), 2.07 (s, 3H), 1.92 (s, 3H), 1.70-1.77 (m, 2H), 1.40-1.49 (m,2H), 0.93 (t, J=7.3 Hz, 3H); MS (ES) m/z 476.08 (M+H).

Step 2: Synthesis of2′-acetyl-3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one(CPD-18). The a stirred mixture of2′-(1-butoxyvinyl)-3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one(CPD-29) (Step 1) was treated at rt with 8 mL of 3 N HCl. After stirringvigorously for 30 min, IPC-HPLC showed no sm remaining). The mixture waspartitioned between EtOAc and brine. The aqueous layer was extractedagain w/EtOAc after neutralizing (K₃PO₄/aq. KOH). The combined organicextract was washed with water, and both aq. phases were back-extractedagain with EtOAc. All of the organic phases were combined and vacuumfiltered through a pad of silica gel. The filtrate was evaporated, andthe residue chromatographed over silica gel with 0-30%2-methytetrahydrofuran in EtOAc. Combined desired fractions,concentrated and dried under high vacuum to afford2′-acetyl-3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one(CPD-18) as an off-white solid, 1.2 g (yield: 75%). ¹H-NMR (400 MHz,DMSO-d6) δ ppm: 8.70 (s, 1H), 8.40 (d, 1H, J=2.4 Hz), 7.78 (s, 1H), 7.34(m, 1H), 6.37 (s, 1H), 5.41 (d, 2H, J=1.6 Hz), 2.73 (s, 3H), 2.18 (s,3H), 1.93 (s, 3H); MS (ES) m/z 420.14 (M+H).

Example 25: Alternative Preparation of2′-acetyl-3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one(CPD-18) from CPD-30

To a stirred suspension of2′-bromo-3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one(CPD-30) (Example 37, 7.0 g, 15.33 mmol), iPr₂NEt (5.3 mL, 30.66 mmol),hydroxyethyl vinyl ether (56.9 mL, 76.64 mmol), NMP (18 mL) and water(18 mL) were charged to a RB flask fitted with a stir bar and condenser,and under N₂. The mixture was warmed with stirring to 45° C. whilebubbling N₂ through mixture. Solid Pd(OAc)₂ (0.1 g, 0.46 mmol, 3 mol %)and dppp (0.38 g, 0.92 mmol, 6 mol %) were added sequentially, and theoil bath was heated to 92° C. Heating at 92-94° C. was continued for 28h, with the reaction progress being monitored by HPLC and TLC.Conversion was very slow initially, so small additional charges ofPd(OAc)₂ were added after about 3 and 21 h of heating. The reaction wasterminated after 28 h of heating, having never been homogeneous. Themixture was cooled and diluted with 2-methyltetrahydrofuran and treatedwith 3 N HCl to ˜pH 2 and stirred vigorously at RT for 30 min. The acidwas neutralized with sat'd KHCO₃ (CO₂ off-gassing), and the product wasextracted into two portions of EtOAc. The combined organic phase waswashed twice with water, then filtered through a pad of silica gel,eluting with EtOAc. Combined desired fractions, concentrated and driedon high vacuum to afford2′-acetyl-3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one(CPD-18) as an off-white solid, 1.4 g (yield: 20%). ¹H-NMR (400 MHz,DMSO-d6) δ ppm: 8.70 (s, 1H), 8.40 (d, 1H, J=2.4 Hz), 7.78 (s, 1H), 7.34(m, 1H), 6.38 (s, 1H), 5.42 (d, 2H, J=1.6 Hz), 2.73 (s, 3H), 2.19 (s,3H), 1.92 (s, 3H); MS (ES) m/z 420.12 (M+H).

Example 26: Alternative Preparation of methyl3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2-oxo-2H-[1,4′-bipyridine]-2′-carboxylate(CDP-05) from CPD-28

To a stirred suspension of2′,3-dichloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one(CPD-28) (Example 41, 50.0 g, 1.0 eq.) in methanol (400 mL, 8.0 vol.)was added TEA (36.8 g, 3.0 eq.) at 25-30° C. and purged with Argon gasfor 30 min. Then added and Pd(dppf)Cl₂ (2.4 g, 0.05 eq.) and purged withargon gas for 30 min. Applied CO pressure 60-70 psi (5 Kg) and releasedpressure. Again pressurized with CO pressure 75-100 psi (7 Kg) andslowly heated reaction mass to 90-95° C. and maintained at the sametemperature for 16 h. The progress of the reaction was monitored byTLC/IPC-HPLC. After completion of the reaction, reaction mass was cooledto room temperature and diluted with DCM (100 mL, 2 vol.) and stirredfor 15-30 min. Thus the resulting reaction mass was filtered throughhyflo bed. Filtrate was distilled under reduced pressure at below 55° C.to afford the crude residue added IPA (250 mL, 5.0 vol.) at 25-35° C.and stirred for 10-12 h and filtered the solid, washed with IPA (50 mL,1 vol.). After drying under vacuum at below 50° C. to afford methyl3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2-oxo-2H-[1,4′-bipyridine]-2′-carboxylate(CPD-05) as a light brown solid, 34.39 g (yield: 66.8%), and HPLC purity95.3%. ¹H-NMR (400 MHz, DMSO-d6) δ ppm: 8.82 (s, 1H), 8.6 (d, J=2.4 Hz,1H), 8.13-8.07 (m, 1H), 8.03 (s, 1H), 6.81 (s, 1H), 5.48 (d, J=1.6 Hz,2H), 3.89 (s, 3H), 1.92 (s, 3H), 1.81 (s, 3H); MS (ES) m/z 436.10 (M+H).

Example 27: Alternative Preparation of methyl3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2-oxo-2H-[1,4′-bipyridine]-2′-carboxylate(CDP-05) from CPD-30

To a stirred solution of2′-bromo-3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one(CPD-30) (Example 38, 3 g, 6.593 mmol, 1 eq) in dry methanol (45 ml, 15vol) in a clean steel bomb was added dppf (182 mg, 0.329 mmol, 0.05 eq)and TEA (2 g, 19.78 mmol, 3 eq) at rt under argon atmosphere. Reactionmass was degassed with argon for 10 minutes followed by the addition ofPd(OAc)₂ (73.9 mg, 0.329 mmol, 0.05 eq) under argon atmosphere. Reactionmass was degassed with argon for 5 minutes. Steel bomb was closed andpressurized with CO gas (100 psi) and released. Again pressurized withCO gas (100 psi) and the reaction mixture was magnetically stirred andheated in oil bath to 80-85° C. for 18 h. The reaction was monitored byIPC-LCMS which showed ˜93.1% desired mass. Reaction mixture was cooledto rt, filtered on celite bed, concentrated filtrate to afford 2.2 gmcrude product. Celite bed was taken in rbf and suspended in 20% MeOH/DCM(100 ml) and stirred for 30 min and filtered. Filtrate was concentratedunder reduced pressure to afford (200 mg) solid. Combined solid wastaken in ethyl acetate (25 ml), stirred for 30 min then filtered anddried to afford methyl3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2-oxo-2H-[1,4′-bipyridine]-2′-carboxylate(CPD-05) as a light brown solid, 2.2 gm (yield: 78%). ¹H-NMR (400 MHz,DMSO-d6) δ ppm: 8.59 (d, J=2.4 Hz, 1H), 8.82 (s, 1H), 8.12-8.02 (m, 2H),7.80 (s, 1H), 6.72 (s, 1H), 5.47 (s, 2H), 3.89 (s, 3H), 2.08 (s, 3H),1.92 (s, 3H); MS (ES) m/z 435.90 (M+H).

Example 28: Alternative Preparation of3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-N-methoxy-N,5′,6-trimethyl-2-oxo-2H-[1,4′-bipyridine]-2′-carboxamide(CDP-16) from CPD-28

To a stirred suspension of2′,3-dichloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one(CPD-28) (Example 41, 500 mg, 1.2165 mmol, 1 eq) in toluene (12.5 mL, 25vol) in a steel bomb was added N,O-dimethylhydroxylamine hydrochloride(237.2 mg, 2.433 mmol, 2 eq), xantphos (28.1 mg, 0.048 mmol, 0.04 eq),and K₃PO₄ (796.6 mg, 3.649 mmol, 3 eq) at rt under argon atmosphere.Reaction mass was degassed with argon for 10 minutes, then Pd(OAc)₂(10.92 mg, 0.0486 mmol, 0.04 eq) was added under argon atmosphere. Thereaction mass was again degassed with argon for 5 minutes. Steel bombwas closed and filled with CO gas (200 psi), the reaction mixture wasmagnetically stirred and heated in oil bath to 120° C. for 3.5 days,IPC-LCMS showed 68.38% of desired material. Reaction mixture was cooledto rt, diluted with EtOAc and filtered through celite bed. Filtrate wasconcentrated and dried under high vacuum to afford3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-N-methoxy-N,5′,6-trimethyl-2-oxo-2H-[1,4′-bipyridine]-2′-carboxamide(CPD-16) as a light brown solid, 248 mg (yield: 45%). MS (ES) m/z 465.21(M+H).

Example 29: Alternative Preparation of3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-N-methoxy-N,5′,6-trimethyl-2-oxo-2H-[1,4′-bipyridine]-2′-carboxamide(CDP-16) from CPD-30

To a stirred suspension of2′-bromo-3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one(CPD-30) (Example 38, 500 mg, 1.098 mmol, 1 eq) in a steel bomb intoluene (25 mL, 50 vol) was added N,O-dimethylhydroxylaminehydrochloride (214.2 mg, 2.197 mmol, 2 eq), xantphos (25.37 mg, 0.0439mmol, 0.04 eq), and K₃PO₄ (719.6 mg, 3.54 mmol, 3 eq) at rt under argonatmosphere. Reaction mass was degassed with argon for 10 minutes, thenPd(OAc)₂ (9.86 mg, 0.0439 mmol, 0.04 eq) was added under argonatmosphere. The reaction mass was again degassed with argon for 5minutes. Steel bomb was closed and filled with CO gas (200 psi) anddegassed, the reaction mixture was magnetically stirred and heated inoil bath to 100-110° C. for 18 h. The reaction was monitored byIPC-LCMS, which showed 71.51% of desired material. Reaction mixture wascooled to rt, diluted with EtOAc and filtered through celite bed. Thecombined organic layer was concentrated under reduced pressure. Thecrude product was purified by Prep-HPLC. Combined desired fractions,concentrated under reduced pressure to remove volatile, basified withAq. NaHCO₃ solution and extracted with DCM, dried over Na₂SO₄concentrated under reduced pressure to afford3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-N-methoxy-N,5′,6-trimethyl-2-oxo-2H-[1,4′-bipyridine]-2′-carboxamide(CPD-16) as an off-white solid, 280 mg (yield: 39.22%). ¹H-NMR (400 MHz,DMSO-d6) δ ppm: 8.70 (s, 1H), 8.59 (d, J=2.4 Hz, 1H), 8.12-8.06 (m, 1H),7.63 (s, 1H), 6.79 (s, 1H), 5.47 (s, 2H), 3.68 (s, 3H), 3.29 (s, 3H),2.05 (s, 3H), 1.93 (s, 3H); MS (ES) m/z 465.16 (M+H).

Example 30: Alternative Preparation of3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-N-methoxy-N,5′,6-trimethyl-2-oxo-2H-[1,4′-bipyridine]-2′-carboxamide(CDP-16) from CPD-15

To a stirred suspension of4-((3,5-difluoropyridin-2-yl)methoxy)-N-methoxy-N,5′,6-trimethyl-2-oxo-2H-[1,4′-bipyridine]-2′-carboxamide(CPD-15) (8.5 g, 19.76 mmol) in IPA (15.0 vol.) was added dichloroaceticacid (0.25 eq.) at 25-30° C. Then heated the reaction mixture to 45-50°C., added a portion wise of N-chlorosuccinimide (1.0 eq.) to thereaction mass at 45-50° C. and heated the reaction mass further to60-65° C. After completion of the reaction (by TLC), Cooled the reactionmass to RT, and further cooled to 0-5° C., filtered the obtained solidand washed with IPA (1 vol.) and dried to afford3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-N-methoxy-N,5′,6-trimethyl-2-oxo-2H-[1,4′-bipyridine]-2′-carboxamide(CPD-16) as a tan solid, 4.5 g (yield: 49%) with HPLC purity 96.43%.¹H-NMR (400 MHz, DMSO-d6) δ ppm: 8.69 (s, 1H), 8.59 (d, J=2.4 Hz, 1H),8.12-8.07 (m, 1H), 7.63 (s, 1H), 6.80 (s, 1H), 5.47 (s, 2H), 3.68 (s,3H), 3.30 (s, 3H), 2.05 (s, 3H), 1.92 (s, 3H); MS (ES) m/z 465.12 (M+H).

Example 31: Preparation of4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2-oxo-2H-[1,4′-bipyridine]-2′-carboxylicacid (CDP-11) from CPD-03

To a solution of2′-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one(CPD-03, Example 5, 1 g, 2.64 mmol, 1 eq) in methanol and water (20 ml,20 vol, 9:1) in a steel bomb with magnetic stirring was added Na₂CO₃(420.8 mg, 3.97 mmol, 1.5 eq) at rt under argon atmosphere. Reactionmass was degassed with argon for 15 minutes. Then Pd(dppf)Cl₂-DCMcomplex (108.53 mg, 0.132 mmol, 0.05 eq) was added under argonatmosphere. Reaction mass was degassed with argon for 5 minutes. Steelbomb was closed and filled with CO gas (50 psi) and released. Againfilled with CO gas (100 psi) and the reaction mixture was magneticallystirred and heated in oil bath to 90-95° C. for 17 h. The reaction wasmonitored by IPC-LCMS until >80% desired product. Reaction mass wascooled to rt, diluted with methanol and filtered through celite bed.Filtrate was concentrated under reduced pressure and crude product wasdiluted with water (20 ml) and washed with ethyl acetate (2×20 ml).Aqueous layer was acidified with 1N aqueous citric acid solution andextracted with 10% MeOH/DCM. The combined organic layer was dried overNa₂SO₄ and evaporated under reduced pressure to afford4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2-oxo-2H-[1,4′-bipyridine]-2′-carboxylicacid (CPD-11) as an off-white solid, 700 mg, (Yield: 71%), HPLC purity99.36%. ¹H-NMR (400 MHz, DMSO-d6) δ ppm: 13.24 (brs, 1H), 8.76 (s, 1H),8.59 (d, 1H, 2.4 Hz), 8.10 (m, 1H), 7.87 (s, 1H), 6.13 (d, 1H, J=2 Hz),6.04 (d, 1H, J=2.4 Hz), 5.24 (s, 2H), 2.08 (s, 3H), 1.82 (s, 3H); LCMS(ES) m/z 387.99 (M+H).

Example 32: Preparation of4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2-oxo-2H-[1,4′-bipyridine]-2′-carboxylicacid (CDP-11) from CPD-26

To a suspension of2′-bromo-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one(CPD-26) (Example 15, Step 2, 200 mg, 0.473 mmol, 1 eq) in methanol andwater (3.6 mL: 0.4 mL, 20 vol, 9:1) was added triethylamine (0.194 mL,1.421 mmol, 3 eq), dppf (13.1 mg, 0.0236 mmol, 0.05 eq) at rt undernitrogen atmosphere. Reaction mass was degassed with argon for 15minutes. Then Pd(OAc)₂ (5.3 mg, 0.0236 mmol, 0.05 eq) was added underargon atmosphere. Reaction mass was degassed with argon for 5 minutesthen the vial was placed in clean, dry Steel bomb. Steel bomb was closedand filled with CO gas (50 psi) and released. Charged with CO gas (100psi) and the reaction mixture was magnetically stirred and heated in oilbath to 90-95° C. for 16 h. The reaction was monitored by LCMS until˜65.2% of desired mass was observed. Pressure was released, vial removedand cooled to rt. Water (0.5 mL) and NaOH (56.7 mg, 1.421 mmol, 3.0 eq)were added and reaction mixture was stirred rt for 16 h and monitored byLCMS until ˜90.6% of desired mass observed. Reaction mixture was dilutedwith methanol and filtered through celite bed. Filtrate was concentratedunder reduced pressure. The crude product was diluted with water (4 mL)and washed with ethyl acetate. Aqueous layer pH adjusted to neutral(6-7) with 1N HCl. Reaction mass was extracted with 20% MeOH/DCM.Evaporated solvent under reduced pressure to afford,4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2-oxo-2H-[1,4′-bipyridine]-2′-carboxylicacid (CPD-11) as a dark brown solid, 150 mg (yield: 81.4%). ¹H-NMR (400MHz, DMSO-d6) δ ppm: 13.22 (brs, 1H), 8.77 (s, 1H), 8.594 (s, 1H), 8.07(t, 1H, J=9.2 Hz), 7.87 (s, 1H), 6.13 (s, 1H), 6.04 (s, 1H), 5.24 (s,1H), 2.08 (s, 3H), 1.98 (s, 3H); MS (ES) m/z 388.17 (M+H).

Example 33: Preparation of3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2-oxo-2H-[1,4′-bipyridine]-2′-carboxylicacid (CDP-06) from CPD-28

To a stirred suspension of2′,3-dichloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one(CPD-28) (Example 41, 25.0 g, 1.0 eq.) in methanol (450 mL, 18.0 vol.)and water (50 mL, 2 vol.) was added Na₂CO₃ (9.64 g, 1.5 eq.) to thereaction mass at 25-30° C. and purged with Argon gas for 30 min. Thenadded and Pd(dppf)Cl₂ (2.4 g, 0.05 eq.) and purged with argon gas for 30min. Then applied CO pressure 60-70 psi (5 Kg) and released CO pressure.Again pressurized with CO pressure 75-100 psi (7 Kg) and slowly heatedreaction mass to 90-95° C. and maintained at the same temperature for 24h. The Progress of the reaction was monitored by TLC/IPC-HPLC. Aftercompletion of reaction, cooled to 25-35° C. and diluted with water (75.0mL 3.0 vol.) and stirred for 20-30 min. Then added charcoal (1.25 g,0.05 T) to the reaction mass and heated to 50-55° C. for 1-2 h. Stoppedheating and the resulting reaction mass was filtered through hyflo bed,distilled-off methanol and reaction mass was diluted with THF (125 mL,5.0 vol.). Then the pH of the reaction mass was adjusted to 1-2 using 6NHCl (60 mL) at 10-15° C. and stirred for 2-3 h, filtered the solid andwashed with water (75 mL, 3 vol.) and dried at 50° C. to afford3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2-oxo-2H-[1,4′-bipyridine]-2′-carboxylicacid (CPD-06) as an off-white solid, 18.0 g (yield: 70.3%). ¹H-NMR (400MHz, DMSO-d6) δ ppm: 8.79 (d, J=10.0 Hz, 1H), 8.60 (d, J=2.4 Hz, 1H),7.98 (s, 1H), 8.12-8.07 (m, 1H), 6.80 (s, 1H), 5.47 (d, J=12.0 Hz, 2H),2.08 (s, 3H), 1.93 (s, 3H); MS (ES) m/z 422.28 (M+H).

Example 34: Preparation of3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2-oxo-2H-[1,4′-bipyridine]-2′-carboxylicacid (CDP-06) from CPD-30

To a stirred suspension of2′-bromo-3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one(CPD-30) (Example 38, 500 mg, 1.098 mmol, 1 eq) in methanol and water(9:1) in a steel bomb was added K₂CO₃ (303 mg, 2.19 mmol, 2 eq), dppf(30 mg, 0.054 mmol, 0.05 eq) at rt under argon atmosphere. Reaction masswas degassed with argon for 10 minutes. Then Pd(OAc)₂ (12.3 mg, 0.054mmol, 0.05 eq), was added under argon atmosphere. Reaction mass wasdegassed with argon for 5 minutes. Steel bomb was closed and filled withCO gas (100 psi) and released. Again pressurized with CO gas (100 psi)and the reaction mixture was magnetically stirred and heated in oil bathto 90-95° C. for 20 h. The reaction was monitored by LCMS which showed˜79.9% desired mass. Reaction mixture was cooled to rt, diluted withmethanol and filtered through celite bed. Organic layer was concentratedunder reduced pressure. The crude compound was taken in RBF thenacidified with 1N HCl to pH ˜2. Solid was filtered and dried to affordcrude desired material. It was purified by prep HPLC. Combined desiredfractions, concentrated under reduced pressure and lyophilized to afford3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2-oxo-2H-[1,4′-bipyridine]-2′-carboxylicacid (CPD-06) as an off-white solid, 200 mg (yield: 43%). ¹H-NMR (400MHz, DMSO-d6) δ ppm: 13.3 (brs, 1H), 8.81 (s, 1H), 8.60 (d, 1H, J=2 Hz),8.12-8.06 (m, 1H), 7.92 (s, 1H), 6.79 (s, 1H), 5.47 (s, 2H), 2.07 (s,3H), 1.92 (s, 3H); MS (ES) m/z 422.10 (M+H).

Example 35: Preparation of3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2-oxo-2H-[1,4′-bipyridine]-2′-carboxylicacid (CDP-06) from CPD-11

To a stirred suspension4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2-oxo-2H-[1,4′-bipyridine]-2′-carboxylicacid (CPD-11) (Example 16, 1.0 g, 2.58 mmol) in IPA (15.0 vol.) andheated to 45-50° C. was added N-chlorosuccinimide (1.0 eq.). Thetemperature was raised 60-65° C. After completion of the reactionindicated by TLC, cooled the reaction mass to RT and then further cooledto 0-5° C., filtered the obtained solid, washed the with IPA (1 vol.)and dried to afford3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2-oxo-2H-[1,4′-bipyridine]-2′-carboxylicacid (CPD-06) as an off-white solid, 0.8 g (yield: 74%). ¹H-NMR (300MHz, DMSO-d6) δ ppm 13.2 (br s, 1H), 8.81 (s, 1H), 8.60 (d, J=2.7 Hz,1H), 8.15-8.06 (m, 1H), 7.98 (s, 1H), 6.80 (s, 1H), 5.48 (s, 2H), 2.07(s, 3H), 1.93 (s, 3H); LC-MS m/z 422.13 (M+H)+.

Example 36: Preparation of4-((3,5-difluoropyridin-2-yl)methoxy)-N-methoxy-N,5′,6-trimethyl-2-oxo-2H-[1,4′-bipyridine]-2′-carboxamide(CDP-15) from CPD-03

To a stirred suspension of2′-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one(CDP-03) (Example 5, Step 1, 5.0 g, 1.0 eq.), in Toluene (10.0 vol.),was added Na₂CO₃ (3.0 eq.). The mixture was degassed with argon gas for30-45 min. Pd(OAc)₂ (0.02 eq.), Xantphos (0.02 eq.), and MeNH(OMe)-HCl(1.5 eq.) were added and the suspension was purged with Argon gas for10-15 min. The temperature was slowly raised to 80° C. and maintainedfor 15 h under CO pressure (60-70 PSI) at the same temperature. Reactionmass was allowed to cool to RT and filtered through celite bed to obtainfiltered mL's that were concentrated under reduced pressure at below 50°C. to afford4-((3,5-difluoropyridin-2-yl)methoxy)-N-methoxy-N,5′,6-trimethyl-2-oxo-2H-[1,4′-bipyridine]-2′-carboxamide(CPD-15), as a tan solid, 4.0 g (yield: 70%). ¹H-NMR (400 MHz, DMSO-d6)δ ppm: 8.65 (brs, 1H), 8.42 (d, 1H, J=2.4 Hz), 7.53 (s, 1H), 7.31 (m,1H), 6.02 (dd, 2H, J=2.4 Hz), 5.18 (d, 2H, J=2 Hz), 3.76 (s, 3H), 3.45(s, 3H), 2.17 (s, 3H), 1.84 (s, 3H); MS (ES) m/z 431.13 (M+H).

Example 37: Preparation of4-((3,5-difluoropyridin-2-yl)methoxy)-N-methoxy-N,5′,6-trimethyl-2-oxo-2H-[1,4′-bipyridine]-2′-carboxamide(CDP-15) from CPD-26

To a stirred suspension of2′-bromo-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one(CPD-26) (Example 15, Step 2, 500 mg, 1.18 mmol, 1 eq) was taken intosteel bomb and suspended in toluene (15 ml, 30 vol).N,O-dimethylhydroxylamine hydrochloride (231 mg, 2.36 mmol, 2 eq),Xantphos (27.28 mg, 0.0472 mmol, 0.04 eq), K₃PO₄ (751 mg, 3.54 mmol, 3eq) were added at rt under nitrogen atmosphere. Reaction mass wasdegassed with argon for 10 minutes. Then Pd(OAc)₂ (10.62 mg, 0.0472mmol, 0.04 eq) was added under N₂ atmosphere. Reaction mass was degassedwith argon for 5 minutes. Steel bomb was closed and filled with CO gas(50 Psi) and released. The reactor was charged with CO gas (50 Psi) andthe reaction mixture was magnetically stirred and heated in oil bath to100-110° C. for 16 h, IPC-LCMS showed ˜65% desired mass. Reactionmixture was cooled to rt, diluted with ethyl acetate and filteredthrough celite bed. The combined organic layer was concentrated underreduced pressure. The crude product was purified by columnchromatography over 230-400 Si-gel, using 2-3% methanol in DCM as aeluent to afford4-((3,5-difluoropyridin-2-yl)methoxy)-N-methoxy-N,5′,6-trimethyl-2-oxo-2H-[1,4′-bipyridine]-2′-carboxamide(CPD-15) as an off-white solid, 250 mg (yield: 42%). ¹H-NMR (400 MHz,DMSO-d6) δ ppm: 8.63 (brs, 1H), 8.40 (d, 1H, J=2.4 Hz), 7.52 (s, 1H),7.31 (m, 1H), 6.02 (dd, 2H, J=2.4 Hz), 5.19 (d, 2H, J=2 Hz), 3.76 (s,3H), 3.44 (s, 3H), 2.17 (s, 3H), 1.86 (s, 3H); MS (ES) m/z 431.06 (M+H).

Example 38: Preparation of2′-bromo-3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one(CDP-30) from CPD-26

To a stirred suspension of2′-bromo-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one(CPD-26) (Example 15, Step 2, 10 g, 23.69 mmol, 1.0 eq) in isopropylalcohol (150 ml, 15 vol) was added N-chlorosuccinimide (3.80 g, 28.43mmol, 1.2 eq) at rt. Reaction mass was slowly heated to 65-70° C. for 2h, while heating slowly clear solution was formed at 55-60° C. Whentemperature reached 65-70° C., solid formation was observed in thereaction. Heating was continued at 65-70° C. for 2 h. Progress of thereaction was monitored by TLC until no starting material remained,reaction mass was cooled to 55-60° C. and filtered while hot. The solidwas washed with IPA (20 ml, 2 vol). Solid was dried under reducedpressure at 45° C. for 2 h to afford2′-bromo-3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one(CPD-30) as an off-white solid, 5.5 g, (yield: 51%). ¹H-NMR (400 MHz,CDCl₃) δ ppm: 8.42 (s, 1H), 8.397-8.391 (d, J=2.4 Hz, 1H), 7.345-7.297(m, 1H), 7.27 (s, 1H), 6.37 (s, 1H), 5.404-5.399 (d, J=2 Hz, 2H), 2.055(s, 3H), 1.973 (s, 3H); MS (ES) m/z 455.96 (M+H).

Example 39: Preparation of2′-bromo-3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one(CDP-30) from CPD-31

To a stirred solution of2′-bromo-3-chloro-4-hydroxy-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one(CPD-31) (Example 40, 15.0 g, 45.45 mmol, 1 eq.) in DMF (75 mL, 5 vol),was added K₂CO₃ (9.42 g, 68.18 mmol, 1.5 eq.) under inert atmosphere.The reaction mixture was stirred for 15 min at room temperature, thenadded 2-(chloromethyl)-3,5-difluoropyridine (INT-01, Example 4) (9.0 g,54.54 mmol, 1.2 eq) in DMF (7.5 ml, 0.5 vol) (drop wise addition) atroom temperature, the resulting reaction mixture was stirred at 50° C.for 7 h. The progress of the reaction was monitored by TLC and LCMS.After completion of the reaction, added ice cold water (25 vol) andstirred for 30 min, then filtered the solid and washed with water. Itwas dried to afford crude desired material as an off-white solid, 21.2g. A suspension of crude desired material (21 g) in methanol (280 mL, 10vol) was heated to reflux, stirred for 45 min to get clear solution. Itwas cooled and stirred at RT for 2 h and the solid was filtered. It waswashed with methanol (28 mL) and dried to afford2′-bromo-3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one(CPD-30) as an off-white solid, 16 g (yield: 77%). ¹H-NMR (400 MHz,DMSO-d6) δ ppm: 8.59 (d, J=2.4 Hz, 1H), 8.52 (s, 1H), 8.09-8.08 (m, 1H),7.80 (s, 1H), 6.92 (s, 1H), 5.47 (s, 2H), 1.95 (s, 6H); MS (ES) m/z455.93 (M+H).

Example 40: Preparation of2′-bromo-3-chloro-4-hydroxy-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one(CDP-31) from CPD-25

To a stirred mixture of2′-bromo-4-hydroxy-5′,6-dimethyl-2H-[1,4′-bipyridine]-2-one (CDP-25)(Example 15, Step 1, 15.0 g, 0.0508 mol, 1 eq) in DMF (255 mL, 15 vol)was added N-chlorosuccinimide (8.1 g, 0.061 mol, 1.2 eq) portion wise at25-30° C. and then reaction mass was heated to 72° C. (oil bath) for 4h. The reaction progress was monitored by TLC and LCMS, which showedabsence of starting material and formation of products. Reaction masswas cooled to RT and water (300 mL, 20 vol) was added, stirred for 45min and the solid was filtered. It was washed with water (75 mL, 5 vol)and dried to afford crude desired material (15.1 g). A suspension ofcrude desired material (15.1 g) in methanol (900 mL, 60 vol) was heatedto reflux, and stirred for 45 min to get a clear solution. It wasfiltered through filter paper and distilled to remove methanol (80%),stirred at RT and the solid was filtered. It was washed with methanol(75 mL, 5 vol) and dried under high vacuum to afford2′-bromo-3-chloro-4-hydroxy-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one(CPD-31) as an off-white solid, 10.2 g (yield: 60.7%). ¹H-NMR (400 MHz,DMSO-d6) δ ppm: 11.59 (s, 1H), 8.49 (s, 1H), 7.75 (s, 1H), 6.15 (s, 1H),1.94 (s, 3H), 1.85 (s, 3H); MS (ES) m/z 329.58 (M+H).

Example 41: Preparation of2′,3-dichloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one(CDP-28) from CPD-03

To a stirred suspension of2′-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one(CPD-03) (Example 5, 100 g, 1.0 eq.) in IPA (1500 mL, 15.0 vol.) wasadded dichloroacetic acid (8.53 g, 0.25 eq.) at room temperature. Thenslowly heated the reaction mass to 45-50° C. and addedN-chlorosuccinamide (NCS, 42.4 g, 1.2 eq.). After completion of additionof NCS, raised the temperature to 65-70° C. and maintained for 2 h, aclear solution was observed at 55-60° C. The progress of the reactionwas monitored by TLC and IPC-HPLC. After completion of the reaction,cooled to 25-35° C., stirred for 1-2 h, filtered, washed with IPA (100mL, 1.0 vol.) and dried at 45° C. for 2-3 h to afford,2′,3-dichloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one(CDP-28), 89.0 g (yield: 81%) with HPLC purity 97.66%. ¹H-NMR (400 MHz,DMSO-d₆) δ ppm: δ: 8.43 (s, 1H), 8.396-8.390 (d, 1H, J=2.4 Hz),7.321-7.301 (m, 1H), 7.12 (s, 1H), 6.379 (s, 1H), 5.4.4-5.40 (d, 2H,J=1.6 Hz), 2.074 (s, 3H), 1.974 (s, 3H); MS (ES) m/z 412.07 (M+H).

Example 42: Alternative Preparation of2′-chloro-4-hydroxy-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one (CPD-02)

Step 1: Synthesis ofN-(2-chloro-5-methylpyridin-4-yl)-2,6-dimethyl-4-oxo-4H-pyran-3-carboxamide(TAUT-01). To a stirred solution of 2-chloro-5-methylpyridin-4-amine(SM-01) (100 g, 1.0 eq.) and 2, 2, 6-trimethyl-4H-1,3-dioxin-4-one(SM-01) (400 g, 4.0 eq.) in dimethyl acetamide (500 mL, 5.0 vol.) washeated to 110-120° C. and maintained for 4-6 h. Progress of the reactionwas monitored by IPC-HPLC. After completion of the reaction, cooled thereaction mass to 40-50° C., quenched with water (15 vol.). Then cooledthe reaction mass to 5-10° C. and stirred for 2-3 h. The solids werefiltered and washed with water (3 vol.) and dried at 50-55° C. to affordbrown color solid 176 g (yield: 85.6%). Based on HPLC data, the ratio ofthe two compoundsN-(2-chloro-5-methylpyridin-4-yl)-2,6-dimethyl-4-oxo-4H-pyran-3-carboxamide(TAUT-01):3-acetyl-2′-chloro-4-hydroxy-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one(CPD-01) are 66.2%: 31.8%. ¹H-NMR (400 MHz, DMSO-d₆): δ ppm.

TAUT-01: ¹H NMR (dmso-d6) S 12.34 (s, 1H), 8.30 (s, 1H), 8.20 (s, 1H),6.49 (s, 1H), 2.74 (s, 3H), 2.34 (s, 3H), 2.26 (s, 3H).

CPD-01: ¹H NMR (dmso-d6) S 15.74 (s, 1H), 8.51 (s, 1H), 7.66 (s, 1H),6.24 (s, 1H), 2.54 (s, 3H), 2.01 (s, 3H), 1.93 (s, 3H), MS (ES) m/z293.68 (M+H).

Step 2: Synthesis of3-acetyl-2′-chloro-4-hydroxy-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one(CPD-01). To a stirred suspension ofN-(2-chloro-5-methylpyridin-4-yl)-2,6-dimethyl-4-oxo-4H-pyran-3-carboxamide(TAUT-01) (Step 1, 100 g, 1.0 eq.) in water (1200 mL, 12 vol.) was added25% IPA-HCl (3.5 vol.) at 25-30° C. and stirred for 30 min. Raised thereaction mass temperature to 80-85° C. and maintained for 14-16 h. Aftercompletion of reaction (by IPC-HPLC) cooled the reaction masstemperature to 5-10° C. and stirred for 2-3 h. Filtered the solid andfurther purified using IPA and water ratio (1:5) at 25-30° C. and driedat 50-55° C. to afford 75.8 g of3-acetyl-2′-chloro-4-hydroxy-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one(CPD-01) as a brown colour powder, (Yield-75.8%) with HPLC purity 98.2%.¹H-NMR (400 MHz, DMSO-d₆): δ ppm 15.74 (s, 1H), 8.52 (s, 1H), 7.67 (s,1H), 6.25 (s, 1H), 2.55 (s, 3H), 2.02 (s, 3H), 1.94 (s, 3H). MS (ES) m/z293.62 (M+H).

Step 3: Synthesis of2′-chloro-4-hydroxy-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one (CPD-02). Toa 3-acetyl-2′-chloro-4-hydroxy-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one(CPD-01) (Step 2, 100 g, 1.0 eq.) was added sulfuric acid (2 vol.) at25-30° C. and resulting suspension was heated to 110-120° C. for 4-6 h.Progress of the reaction was monitored by IPC-HPLC. After completion ofthe reaction, stopped heating and cooled the reaction mass to 25-30° C.Reaction mass was diluted with water (15 vol.), further cooled to 5-10°C. and pH was adjusted to 8-9 with aq. NaOH solution. Then pH of theresulting reaction mass was again adjusted to 3.5-4.5 using sat. citricacid. Thus obtained solid was filtered washed with water (3 vol.), MTBE(5 vol.), Further slurry purified by DMF (5 vol.) and water (5 vol.),dried at 50-55° C. to afford2′-chloro-4-hydroxy-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one (CPD-02) asa brown color solid 52 g (yield: 60.7%) with HPLC purity 99.3%. ¹H-NMR(400 MHz, DMSO-d₆): δ ppm 10.8 (br s, 1H), 8.47 (s, 1H), 7.55 (s, 1H),5.97-5.96 (m, 1H), 5.57 (d, J=2.4 Hz, 1H), 1.96 (s, 3H), 1.83 (s, 3H).MS (ES) m/z 251.52 (M+H).

Example 43: Kinetic Dynamic Resolution of the Atropisomers of CPD-06

Step 1: Synthesis of (P & M)3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2-oxo-2H-[1,4′-bipyridine]-2′-carboxylicacid (S)-1-(naphthalen-2-yl)ethan-1-aminium (Isomer 1 Salt A and Isomer2 Salt A) salt. To a stirred suspension of3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2-oxo-2H-[1,4′-bipyridine]-2′-carboxylicacid (CPD-06) (10 g) in Ethanol (20 vol.) in RBF and slowly heated to25-35° C. then added (S)-(−)-1-2-Napthylethyl amine (1.0 eq.) 25-35° C.(Observation: after addition of (S)-(−)-1-2-Napthylethyl amine, clearsolution was observed and immediately precipitation observed) andstirred for 24 h at 25-35° C., filtered the solid, and dried to afford a1:1 diastereomeric salt mixture of (P & M)3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2-oxo-2H-[1,4′-bipyridine]-2′-carboxylicacid (S)-1-(naphthalen-2-yl)ethan-1-aminium (Isomer 1 Salt A and Isomer2 Salt A) salt as a white solid, 13.7 g (yield: 97%).

Step 2: Synthesis of(P)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2-oxo-2H-[1,4′-bipyridine]-2′-carboxylicacid (S)-1-(naphthalen-2-yl)ethan-1-aminium (Isomer 1 Salt A). The 1:1diastereomeric salt mixture of (P & M)3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2-oxo-2H-[1,4′-bipyridine]-2′-carboxylicacid (S)-1-(naphthalen-2-yl)ethan-1-aminium (Isomer 1 Salt A and Isomer2 Salt A) salt (Step 1) was taken in toluene (20.0 vol.) and slowlyheated to 120-130° C. and the suspension was maintained for 96 h. TheIPC-Chiral HPLC shows 96.66%. Reaction was cooled to RT and thesuspension was filtered and washed solid with MTBE and dried undervacuum to afford(P)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2-oxo-2H-[1,4′-bipyridine]-2′-carboxylicacid (S)-1-(naphthalen-2-yl)ethan-1-aminium (Isomer 1 Salt A) as a whitesolid. Material was used as is for Step 3.

Step 3: Synthesis of(P)-3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2-oxo-2H-[1,4′-bipyridine]-2′-carboxylicacid (CPD-07). The resulting chiral amine salt,(P)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2-oxo-2H-[1,4′-bipyridine]-2′-carboxylicacid (S)-1-(naphthalen-2-yl)ethan-1-aminium (Isomer 1 Salt A) (Step 2,13.0 g) was dissolved in water (6.0 mL) and basified with 2N NaOH to pH˜12 and extracted with MTBE (2×10.0 vol.). The resulting MTBE layercontaining the amine was distilled to afford (S)-(−)-1-2-Napthylethylamine with 97.41% of HPLC purity. The aqueous layer was acidified to pH˜2 with 2N HCl and solid precipitation was observed. The precipitatedsolid was filtered, washed and dried under vacuum to afford(P)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2-oxo-2H-[1,4′-bipyridine]-2′-carboxylicacid (CPD-07) as an off-white solid, 9.36 g (yield=72%) with 98.53% ofHPLC purity and 99.77% of chiral HPLC purity. ¹H-NMR (300 MHz, DMSO-d6):δ ppm 13.35 (br s, 1H), 8.80 (s, 1H), 8.60 (d, 1H, J=2.4 Hz), 8.07-8.12(m, 1H), 7.97 (s, 1H), 6.80 (s, 1H), 5.47 (d, 2H, J=1.6 Hz), 2.08 (s,3H), 1.93 (s, 3H). MS (ES) m/z 422.12 (M+H).

Example 44: Chiral Purification of CPD-20 Via Simulated Moving Bed (SMB)Chromatography

CPD-20 was screened for chiral purification by Simulated Moving Bed(SMB) chromatography. The separation was conducted with parameters foundin Table 4. The final separation operating pressure was 9 bar. Theseparation of racemic CPD-20 to obtain each atropisomer was demonstratedusing Chiralpak® IB-N, 20 m, as the stationary phase and 50/50 DCM/ACNv/v as the mobile phase on a bench-top SMB unit. The SMB unit isequipped with 8 columns of 10 cm in length and 1 cm in diameter. Theatropisomers were separated into two process streams, the raffinate(Formula (P)-I) and the extract (Formula (M)-I). Compound Formula (P)-Iwas recovered in the raffinate stream.

TABLE 4 SMB Parameters Eluent Chiral Purity (%) Run (Cycle#) Zone 1Extract F Raffinate flow rate Period Extract Raffinate Start (0) 9.9 7.30.6 1.8 8.5 2.73 97.9 100 End (345) 8.5 5.9 0.6 1.8 7.2 2.83 99.9 100

Feed Preparation: A feed solution was prepared using CPD-20. A total of40.3 grams of crude feed were dissolved to 0.8 liter with 50/50,DCM/ACN. The solution was tested against a known standard to determinethe concentration; 50 g/l.

Example 45: Kinetic Dynamic Resolution of the Atropisomers of CPD-06 inn-Butanol

Synthesis of (P & M)3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2-oxo-2H-[1,4′-bipyridine]-2′-carboxylicacid (S)-1-(naphthalen-2-yl)ethan-1-aminium (Isomer 1 Salt A and Isomer2 Salt A) To the stirred suspension of (P & M)3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2-oxo-2H-[1,4′-bipyridine]-2′-carboxylicacid HPLC chiral purity (Isomer 1: Isomer 2, 98.7%:1.3%) (Example 43Step 1, 1.0 eq.) in 1-butanol (15.0 vol.) was added (S)-2-Napthylethylamine (1.0 eq.) at 25-35° C. The reaction mixture was slowly heated to110-115° C. and stirred for 40 hours at 110-115° C. The progress of theresolution was monitored by chiral HPLC. After completion of theresolution, the reaction mixture was cooled to 25-35° C., stirred for3-4 hours at 25-35° C. Filtered the solid and dried the solid undervacuum below 45° C. to afford (P & M)3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2-oxo-2H-[1,4′-bipyridine]-2′-carboxylicacid (S)-1-(naphthalen-2-yl)ethan-1-aminium chiral HPLC purity (Isomer 1Salt A: Isomer 2 Salt A, 99.3%:0.70%), 5.5 g (yield: 78.3%). ¹H-NMR (400MHz, DMSO-d6): δ ppm 8.66 (s, 1H), 8.60 (d, J=2.0 Hz, 1H), 8.09 (td,J=2.4, 10.0 Hz, 1H), 7.96-7.88 (m, 6H), 7.78 (s, 1H), 7.63 (d, J=7.0 Hz,1H), 7.52 (t, J=3.6 Hz, 3H), 6.77 (s, 1H), 5.41 (s, 2H), 4.46 (brs, 1H),2.02 (s, 3H), 1.91 (s, 3H), 1.53 (d, J=6.4 Hz, 3H). MS(ES) m/z 422.28(M+H).

Example 46: Alternative preparation of3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2-oxo-2H-[1,4′-bipyridine]-2′-carboxylicAcid (CDP-06) from CPD-28

To a stirred suspension of2′,3-dichloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one(CPD-28) (Example 41, 76.0 g, 1.0 eq.) in acetonitrile (8.0 vol.) andwater (4.0 vol.). Then purged with argon gas for 30 min. and was addedLi2CO3 (3.0 eq.) followed by Pd(dppf)Cl₂ (0.5 mol. %.) to the reactionmass and purged with argon gas for 30 min. Then applied CO pressure40-45 PSI (3.0 Kg) and released CO pressure. Again, applied CO pressure100 PSI (5.0 Kg) and slowly heated to 75° C. and stirred for 48 h. Theprogress of the reaction was monitored by TLC/IPC-HPLC, after reactioncompletion the reaction was cooled to 25-30° C. and de-gas with argon.Unloaded the reaction mass and added water (5.0 vol.) and adjusted pH to14 with 2N NaOH solution. Then reaction mass was washed with MTBE (3×5.0vol.) and aqueous layers were filtered through high flow bed. The pH offiltered mL's was adjusted to 1-2 with 6N HCl and stirred for 1-2 h at25-30° C. Filtered the solid, washed with water (10.0 vol.) followed byIPA (1.0 vol.) and dried under vacuum to afford 67.5 g (yield: 86.80%)3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2-oxo-2H-[1,4′-bipyridine]-2′-carboxylicacid (CPD-06) as an off-white solid with HPLC purity of 98.49%. ¹H-NMR(400 MHz, DMSO-d6) δ ppm: 13.35 (br s, 1H), 8.80 (s, 1H), 8.60 (d, 1H,J=2.4 Hz), 8.07-8.12 (m, 1H), 7.97 (s, 1H), 6.80 (s, 1H), 5.47 (d, 2H,J=1.6 Hz), 2.08 (s, 3H), 1.93 (s, 3H). MS (ES) m/z 422.28 (M+H).

Example 47: Alternative preparation of (P & M)3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2-oxo-2H-[1,4′-bipyridine]-2′-carboxylicacid (S)-1-(naphthalen-2-yl)ethan-1-aminium (Isomer 1 Salt A and Isomer2 Salt A) Salt

A stirred suspension of3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2-oxo-2H-[1,4′-bipyridine]-2′-carboxylicacid (CPD-06) (25 g, 1.0 eq.) in 5% of DMSO: anisole (7.04 vol.) wasslowly heated to 110-115° C. Then slowly added3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2-oxo-2H-[1,4′-bipyridine]-2′-carboxylicacid (0.025 eq., Seed HPLC chiral purity Isomer I, Isomer 2,99.91%:0.09%) to the reaction mass and stirred for 10-15 min. followedby the addition (S)-2-Napthylethyl amine (1.04 eq., 4.05 g) in DMSO:anisole (14 vol., 60 mL) using syringe pump with flow rate (35 mL per 1h) for 20 h. The progress of reaction was monitored by Chiral HPLC andstirred for 64 h. Cooled to 25-30° C. and stirred for 1-2 h. Filteredthe solid, washed with ethanol (10 vol.) and dried under vacuum toafford 32.07 g (yield: 91.6%) of (P & M)3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2-oxo-2H-[1,4′-bipyridine]-2′-carboxylicacid (S)-1-(naphthalen-2-yl)ethan-1-aminium (Isomer 1 Salt A and Isomer2 Salt A) salt. The salt (32 g) was added to water (10 vol.) and pH wasadjusted to 12-14 with 2.0 N NaOH solution and aqueous layers werewashed with MTBE (3×5 vol.). Then pH of the aqueous layer was adjustedto 0.5-1.0 with 6.0 N HCl and the resulting precipitated solid wasstirred for 2-5 h. Filtered the solid and washed with IPA (1 vol.) anddried under vacuum to afford free acid 19.0 g (yield: 83.5%) of(P)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2-oxo-2H-[1,4′-bipyridine]-2′-carboxylicacid (CPD-07) as an off-white solid, with 99.62% of HPLC purity and HPLCchiral purity (Isomer 1: Isomer 2, 99.41%:0.59%). ¹H-NMR (400 MHz,DMSO-d6): δ ppm 13.35 (br s, 1H), 8.80 (s, 1H), 8.60 (d, 1H, J=2.4 Hz),8.07-8.12 (m, 1H), 7.97 (s, 1H), 6.80 (s, 1H), 5.47 (d, 2H, J=1.6 Hz),2.08 (s, 3H), 1.93 (s, 3H). MS (ES) m/z 422.12 (M+H).

Example 48: Alternative preparation of(P)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-N-methoxy-N,5′,6-trimethyl-2-oxo-2H-[1,4′-bipyridine]-2′-carboxamide(CPD-08)

To a stirred suspension of(P)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2-oxo-2H-[1,4′-bipyri-dine]-2′-carboxylicacid (CPD-07) (117.0 g, 1.0 eq, Isomer I, Isomer 2, 97.86%:2.14%) in DCM(8 vol.) at −5 to 0° C. was added1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC•HCl (1.1 eq.)) at −5to 0° C., and it was stirred for 5-10 min. TEA (1.0 eq.) was added at0-5° C., and the mixture was stirred for 10-20 min. Then N, O-dimethylhydroxylamine hydrochloride (1.5 eq.) was added at −5 to 0° C. followedby the addition of TEA (1.25 eq) at −5 to 0° C. and stirred for 1-2 h,the progress of the reaction was monitored by TLC and IPC-HPLC. Aftercompletion of the reaction ice-cold water (20.0 vol.) was added andreaction was allowed to warm to 25-35° C., stirred for 10 min. andseparated DCM layer. Aqueous later was extracted with DCM (2×5 vol.) andcombined DCM layers were washed with water (5 vol.), dried with Na₂SO₄.The DCM layer was completely distilled and Co-distilled with MTBE (3×3vol.) followed by residue precipitation with MTBE (5 vol.) and stirredfor 2-3 h. Filtered the solid, washed with MTBE (1 vol.) and dried toafford 121.0 g (yield: 93.86%) of(P)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-N-methoxy-N,5′,6-trimethyl-2-oxo-2H-[1,4′-bipyridine]-2′-carboxamidewith HPLC purity 99.13% along with HPLC Chiral purity (Isomer 1: Isomer2, 97.14%:2.86%). ¹H-NMR (400 MHz, DMSO-d6): δ ppm 8.70 (s, 1H), 8.59(d, 1H, J=2.4 Hz), 8.04-8.12 (m, 1H), 7.63 (s, 1H), 6.79 (s, 1H), 5.47(d, 2H, J=1.6 Hz), 3.67 (s, 3H), 3.29 (s, 3H), 2.04 (s, 3H), 1.93 (s,3H); MS (ES) m/z 465.31 (M+H).

Example 49: Alternative preparation of(P)-2′-Acetyl-3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one(CPD-09)

To a stirred solution of(P)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-N-methoxy-N,5′,6-trimethyl-2-oxo-2H-[1,4′-bipyridine]-2′-carboxamide(CPD-08) (115.0 g, Isomer 1: Isomer 2 (97.14%:2.86%) in dry THF (42vol.) was slowly added MeMgCl (1.2 eq.; 3M solution in THF) at −10° C.to 0° C. and stirred for 1-1 h. Then the reaction mass temperature wasraised to 0-5° C. and maintained for 1 h. The progress of the reactionwas monitored by TLC and IPC-HPLC. After completion the reaction wasquenched with 10% aq. ammonium chloride solution (10 vol.). The organiclayer was distilled under vacuum at below 40° C. Water (2 vol.) wasadded and the reaction was stirred for 2-4 h at 25-30° C. The solid wasfiltered, washed with water (5 vol.) followed by IPA (1.0 vol.) anddried under vacuum at below 40° C. to afford 94.18 g (yield: 90.7%) of(P)-2′-Acetyl-3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-onewith HPLC purity 96.61% and HPLC chiral purity (Isomer 1: Isomer 2,98.06%:1.94%). ¹H-NMR (400 MHz, DMSO-d6): δ ppm 8.83 (s, 1H), 8.59 (d,1H, J=2.4 Hz), 8.05-8.14 (m, 1H), 7.89 (s, 1H), 6.79 (s, 1H), 5.47 (d,2H, J=1.6 Hz), 2.66 (s, 3H), 2.09 (s, 3H), 1.91 (s, 3H); MS (ES) m/z420.08 (M+H).

Example 50: Alternative preparation of(P)-(E)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-2′-(3-(dimethyl-amino)acryloyl)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one(CPD-10)

To a stirred solution of(P)-2′-Acetyl-3-chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one(CPD-09) (5.5 g, 1.0 eq., Isomer 1: Isomer 2, 95.28%: 4.72%), was addedN,N-dimethyl-formamide dimethyl acetal (DMF-DMA (6.0 eq.)) and DMF (1.0vol.) at 25-35° C. The reaction mass was slowly heated to 50-55° C. andmaintained for at that temperature for 24 h. Progress of the reactionwas monitored by TLC and IPC-HPLC. After completion of reaction, heatingwas stopped and the mixture was cooled to 25-35° C. and stirred for 1-2h. Filtered solid and washed with EtOAc (2.0 vol.) and dried undervacuum at below 40° C. to afford 4.6 g (yield: 74.0%) of(P)-(E)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-2′-(3-(dimethyl-amino)acryloyl)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-onewith HPLC 98.74%, and HPLC chiral purity (Isomer 1: Isomer 2(99.92%:0.08%). ¹H-NMR (400 MHz, DMSO-d6): δ ppm 8.71 (s, 1H), 8.60 (d,1H, J=2.4 Hz), 8.04-8.12 (m, 1H), 7.80-7.86 (m, 2H), 6.78 (s, 1H), 6.37(d, 1H, J=12.8 Hz), 5.47 (d, 2H, J=1.6 Hz), 3.19 (s, 3H), 2.94 (s, 3H),2.05 (s, 3H), 1.91 (s, 3H); MS (ES) m/z 475.36 (M+H).

Example 51: Alternative preparation of(P)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-2′-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one(Formula P-(I))

To a stirred solution of(P)-(E)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-2′-(3-(dimethyl-amino)acryloyl)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one(CPD-10) (4.0 g, 1.0 eq., Isomer 1: Isomer 2, 99.85%:0.15%) in DMF (6.0vol.) was added portion wise K₂CO₃ (2.5 eq.). followed by the additionof 2-hydroxy-2-methylpropionamidine HCl (INT-02) (3.0 eq.) at 25-35° C.The reaction mass was slowly warmed to 45-50° C. and was stirred at thattemperature for 40 h. Progress of the reaction was monitored by TLC/IPCHPLC. After the reaction was completed, it was cooled to 25-35° C.,diluted with water (15 vol.), and stirred for 1-2 h, further cooled to0-10° C. and stirred for 3-4 h. The solid was filtered, washed withwater (2.0 vol.). Then solid was dissolved in DCM (10.0 vol.) andcharged activated carbon (0.5 T) and stirred for 1-2 h at 35-40° C.Filtered the Reaction mass on Hi-flow bed washed with DCM (2.0 vol.).Distilled the Filtered mL's under vacuum at below 40° C., co-distilledwith IPA (2.0 vol.) and charged IPA (19.0 vol.) then heated to 72-77°C., stirred for 1-2 h at 72-77° C. Slowly cooled to 25-30° C. andfurther cool to 7-15° C., stirred for 2-4 h. Filtered the solid anddried under vacuum at below 40° C. to afford 2.58 g (yield: 60.0%)(P)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-2′-(2-(2-hydroxy-propan-2-yl)pyrimidin-4-yl)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one,with HPLC purity 99.65% and HPLC chiral purity (Isomer 1: Isomer 2)(98.86%: 1.14%).

Example 52: Crystallization of(P)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-2′-(2-(2-hydroxypropan-2-yl)pyrimidin-4-yl)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one(Formula P-(I))

To a stirred suspension of(P)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-2′-(2-(2-hydroxy-propan-2-yl)-pyrim-idin-4-yl)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-one(Formula P-(I)) (1.0 g, 1.0 eq., Isomer 1: Isomer 2 (98.86%:1.14%) inIPA (19.0 vol.) was stirred for 1 h at 72-77° C. Seed material (FormulaP-(I)) (0.25 g, 0.05 w/w times) was then added at 72-77° C. Heating wasstopped and the mixture was allowed to cool to 25-35° C. After stirringfor 24 h the solid was filtered. The solid was washed with IPA (2.0vol.), and it was dried at below 40° C. to afford 0.8 g (yield: 80%) of(P)-3-Chloro-4-((3,5-difluoropyridin-2-yl)methoxy)-2′-(2-(2-hydroxypropan-2-yl)-pyrimidin-4-yl)-5′,6-dimethyl-2H-[1,4′-bipyridin]-2-onewith HPLC purity 99.52% and HPLC chiral purity (Isomer 1: Isomer 2,99.65%:0.35%). ¹H-NMR (400 MHz, DMSO-d₆): δ ppm 8.97 (d, 1H, J=5.2 Hz),8.86 (s, 1H), 8.69 (s, 1H), 8.61 (d, 1H, J=2.4 Hz), 8.24 (d, 1H, J=5.2Hz), 8.06-8.14 (m, 1H), 6.84 (s, 1H), 5.49 (d, 2H, J=1.2 Hz), 5.25 (s,1H), 2.10 (s, 3H), 1.98 (s, 3H), 1.04 (s, 3H), 1.03 (s, 3H); MS (ES) m/z514.37 (M+H).

1.-203. (canceled)
 204. A process for the preparation of CPD-30 havingthe structure: comprising contacting the compound

with a chlorination reagent to form CPD-30.


205. A process for the preparation of CPD-30 having the structure:

comprising the steps of (a) contacting the compound

with a chlorination reagent to form the compound

and (b) contacting the compound CPD-31 with the compound

and a base to form the compound CPD-30.
 206. A process for thepreparation of CPD-18 having the structure:

comprising the steps of (a) contacting the compound

with butyl vinyl ether in the presence of a palladium catalyst, aphosphorus reagent, and a base to form the compound

and (b) contacting CPD-29 with an acid to form CPD-18.
 207. A processfor the preparation of CPD-18 having the structure:

comprising the steps of (a) contacting the compound

with hydroxyethyl vinyl ether in the presence of a palladium catalyst, aphosphorus reagent, and a base to form a mixture; and (b) contacting themixture of (a) with an acid to form the compound CPD-18.
 208. A processfor the preparation of CPD-18 having the structure.

comprising the steps of (a) contacting the compound

with a vinyl tin reagent in the presence of a palladium catalyst to forma mixture; and (b) contacting the mixture of (a) with an acid to formthe compound CPD-18.
 209. A process for the preparation of CPD-18 havingthe structure:

comprising the steps of (a) contacting the compound

with butyl vinyl ether in the presence of a palladium catalyst, aphosphorus reagent, and a base to form the compound

and (b) contacting CPD-28 with an acid to form CPD-18.
 210. A compound,or a salt thereof, or a co-crystal thereof, selected from the groupconsisting of:


211. The compound of claim 210, or a co-crystal thereof, wherein thecompound is:


212. The compound of claim 210, or a co-crystal thereof, wherein thecompound is:


213. The compound of claim 210, or a co-crystal thereof, wherein thecompound is:


214. The compound of claim 210, or a co-crystal thereof, wherein thecompound is:


215. The compound of claim 210, or a co-crystal thereof, wherein thecompound is: